US8039273B2 - β-glucuronide-linker drug conjugates - Google Patents

β-glucuronide-linker drug conjugates Download PDF

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US8039273B2
US8039273B2 US11/996,009 US99600906A US8039273B2 US 8039273 B2 US8039273 B2 US 8039273B2 US 99600906 A US99600906 A US 99600906A US 8039273 B2 US8039273 B2 US 8039273B2
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drug conjugate
antibody
ligand
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Scott Jeffrey
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Seagen Inc
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Seattle Genetics Inc
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Priority to US15/463,267 priority patent/US20170189542A1/en
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    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Definitions

  • Monoclonal antibody therapies are gaining momentum as adjunct and front-line treatments for cancer.
  • Successes of mAb therapies like AVASTIN (anti-VEGF) for colon cancer, RITUXAN (Rituximab; anti-CD20) for Non-Hodgkin's Lymphoma and HERCEPTIN (anti-Her2) for breast cancer have demonstrated that unconjugated antibodies can improve patient survival without the incidence of significantly increased toxicity.
  • Monoclonal antibodies can be conjugated to a therapeutic agent to form an antibody drug conjugate (ADC).
  • ADCs can exhibit increased efficacy, as compared to an unconjugated antibody.
  • the linkage of the antibody to the drug can be direct, or indirect via a linker.
  • One of components believed to be important for developing effective and well-tolerated ADCs is the composition and stability of the linker.
  • the linker desirably provides serum stability, yet selectively releases the drug at or within the target cell.
  • Attachment of a linker to a mAb can be accomplished in a variety of ways, such as through surface lysines, reductive-coupling to oxidized carbohydrates, and through cysteine residues liberated by reducing interchain disulfide linkages.
  • a variety of ADC linkage systems have been described in the literature, including hydrazone-, disulfide- and peptide-based linkages. Some hydrazone and disulfide-based linkers can be labile in circulation, resulting in release of drug outside the targeted tissue. It is believed that this premature release of drug might lead to systemic toxicity or organ-specific toxicity and/or less than optimal therapeutic efficacy.
  • Peptide-based linker strategies may provide linkers of higher stability; however, the increased associated hydrophobicity of some linkers may lead to aggregation, particularly with strongly hydrophobic drugs. Such aggregation may lead to non-specific uptake of the ADCs into non-targeted tissues, potentially affecting non-target toxicity.
  • ⁇ -glucuronides are metabolites produced in the liver and kidneys by a class of enzymes known as UDP-glucuronosyl transferases. These transferases are involved in a metabolic transformation leading to the clearance of xenobiotics from the body. Glucuronidation dramatically increases the solubility of substrate compounds, allowing more efficient renal clearance.
  • ⁇ -glucuronidase is a UDP-glucuronosyl transferase which is present in the lysosomes of essentially all human tissues.
  • the enzyme catalyzes the hydrolysis of the glycosidic bond of glucuronides with ⁇ -configuration and is reported to have broad substrate specificity. It is most active at a low pH with the enzymatic efficiency dropping to approximately 10% at neutral pH.
  • ⁇ -glucuronidase has been reported to be over-expressed in breast cancer tissue relative to peritumor tissue. In spite of its ubiquitous nature, the enzyme is effectively sequestered inside cell lysosomes, and minimal immunohistochemical staining is observed in the extracellular space of normal tissue samples.
  • One exception is the ⁇ -glucuronidase activity seen in the intestinal tract, arising from the presence of E. coli.
  • ⁇ -glucuronide prodrugs primarily of doxorubicin
  • the rationale for this approach is that the ⁇ -glucuronide prodrug would be less toxic than free drug due to its inability to enter cells.
  • the prodrug has two primary fates: prodrug in the vicinity of the tumor will be converted to free drug, while the remaining prodrug will be rapidly cleared through the kidneys.
  • ADEPT Antibody Directed Enzyme Pro-drug Therapy
  • the present invention provides ligand drug conjugates and linker-drug conjugates for targeted delivery of drugs.
  • the ligand drug conjugates include a ligand, such as an antibody, for targeting the conjugate to a target cell or tissue.
  • the conjugates further include a ⁇ -glucuronide-based linker comprising a site that can be cleaved by an enzyme having ⁇ -glucuronidase activity.
  • the linker is attached to the ligand and to a drug.
  • the invention further provides methods of treating cancer, immune disease, infectious disease and other diseases or disorders using a ligand drug conjugate including a ⁇ -glucuronide-based linker.
  • the ligand drug conjugates surprisingly yet exhibit serum stability to provide targeted delivery of linked drug to a target cell.
  • a ligand drug conjugate compound having the following formula:
  • the Ligand is an antibody, such as a chimeric, humanized or human antibody or an antigen binding antibody fragment.
  • the Glucuronide unit (—W—) comprises the formula:
  • S is sugar moiety
  • —O′— is a glycosidic bond (e.g., cleavable by a ⁇ -glucuronidase) and Z is a self-immolative group; and wherein Z forms a first covalent bond with Y or D and a second covalent bond with L or A.
  • the Glucuronide unit (—W—) comprises the formula: -Su-O′—Z— wherein S is sugar moiety, —O′— is a bond cleavable by a ⁇ -Glucuronidase and Z is a self-immolative group; and wherein Z forms a covalent bond with Y or D and Su forms a covalent bond with L or A.
  • the Drug unit is selected from Formulas D E and D F :
  • the Drug unit is Formula D F :
  • the Drug unit has the formula:
  • the Drug unit has the formula D E :
  • the Drug unit has the formula:
  • the ligand drug conjugate compound has the following formula:
  • the ligand drug conjugate compound has the formula:
  • the ligand drug conjugate compounds can be formulated as a pharmaceutical composition comprising an effective amount of the ligand drug conjugate compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.
  • the pharmaceutical composition optionally can include therapeutically effective amount of chemotherapeutic agent.
  • a method of killing or inhibiting the proliferation of tumor cells or cancer cells generally include treating tumor cells or cancer cells with an amount of the ligand drug conjugate compound, or a pharmaceutically acceptable salt or solvate thereof, being effective to kill or inhibit the proliferation of the tumor cells or cancer cells.
  • a method for treating cancer generally includes administering to a patient an amount of the antibody-drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof, the amount being effective to treat cancer.
  • the method can optionally include administering an effective amount of an additional anticancer agent, an immunosuppressant agent or an anti-infectious agent.
  • a method for treating an autoimmune disease includes administering to a patient an amount of ligand drug conjugate compound, or a pharmaceutically acceptable salt or solvate thereof, the amount being effective to treat the autoimmune disease.
  • a method for treating an infectious disease generally includes administering to a patient an amount of the ligand drug conjugate compound or a pharmaceutically acceptable salt or solvate thereof, the amount being effective to treat the infectious disease.
  • FIG. 1 shows the reactivity of a cysteine-quenched Glucuronide linker-MMAF conjugate with E. coli ⁇ -glucuronidase. Cysteine-quenched c1F6-9b was added to the enzyme and incubated at 37° C. Hydrolysis to free drug was monitored by HPLC (254 nm) with sampling every 30 min. Digestion half-life was 41 min.
  • FIG. 2 shows in vitro cytotoxic activity of ADCs on CD30+ and CD70+ cancer cell lines:
  • A Karpas 299 (CD30+) ALCL cells treated with anti-CD30 ADC cAC10-9a and non-binding control c1F6-9a for 96 hours.
  • B 786-O (CD70+) RCC cells treated with anti-CD70 ADC c1F6-9b and non-binding control cAC10-9b for 96 hours.
  • C Caki-1 (CD70+) RCC cells treated with c1F6-17 and nonbinding control cAC10-17. Results are shown as mean ⁇ SD.
  • FIG. 3 shows in vivo studies with ADCs.
  • Panel A shows the effect of cAC10-9a (with MMAE) on CD30+ Karpas 299 (ALCL) subcutaneous tumor bearing SCID mice.
  • a dose of 3 mg/kg of non-binding control conjugate c1F6-9a ( ⁇ ) resulted in no tumor response as with the untreated group ( ⁇ ).
  • Panel B shows the effect of c1F6-9b (with MMAF) on CD70+ 786-O (RCC) subcutaneous tumor bearing SCID mice.
  • trade names includes the trade name product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.
  • antibody herein is used in the broadest sense and refers to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and to antibody fragments that exhibit the desired biological activity (e.g., antigen binding).
  • the antibody can be of any type or class (e.g., IgG, IgE, IgM, IgD, and IgA) or sub-class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2).
  • an “intact” antibody is one which comprises an antigen-binding variable region as well as a light chain constant domain (C L ) and heavy chain constant domains, C H 1, C H 2, C H 3, and/or C H 4, as appropriate for the antibody class.
  • the constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variant thereof.
  • An antibody may have one or more “effector functions” which refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody.
  • effector functions include C1q binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc.
  • Single-chain Fv or “scFv” antibody fragments comprise the V H and V L domains of an antibody, wherein these domains are present in a single polypeptide chain.
  • the F v polypeptide typically further comprises a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
  • diabody refers to a small antibody fragment with two antigen-binding sites, which fragment comprises a variable heavy domain (V H ) connected to a variable light domain (V L ) in the same polypeptide chain.
  • V H variable heavy domain
  • V L variable light domain
  • the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • Diabodies are described more fully in, for example, EP 0 404 097; WO 93/11161; and Hollinger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448.
  • the two antigen-binding sites can be the same or different.
  • an “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
  • the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, or to greater than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
  • An antibody “which binds” an antigen of interest is one capable of binding that antigen with sufficient affinity such that the antibody is useful in targeting a cell expressing the antigen.
  • the terms “specifically binds” and “specific binding” refer to antibody binding to a predetermined antigen.
  • the antibody binds with an affinity of at least about 1 ⁇ 10 7 M ⁇ 1 , and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
  • a non-specific antigen e.g., BSA, casein
  • terapéuticaally effective amount refers to an amount of a drug (e.g., a ligand drug conjugate or linker drug conjugate) effective to treat a disease or disorder in a mammal.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • target polypeptide refers to a protein, polypeptide, and in addition in the case of a “target antigen,” another molecule on the surface of or associated with a target cell.
  • salts of the compound preferably pharmaceutically acceptable salts, including acid addition salts and base addition salts, including salts having organic counterions and inorganic counterions, and including zwitterionic forms, where if a compound is associated with two or more counterions, the two or more counterions may be the same or different; and solvates of the compound, including hemisolvates, monosolvates, disolvates, etc., including organic solvates and inorganic solvates, said inorganic solvates including hydrates; where if a compound is associated with two or more solvent molecules, the two or more solvent molecules may be the same or different.
  • reference made herein to a compound of the invention will include an explicit reference to one or of the above forms, e.g., salts and solvates, however, this reference is for emphasis only, and is not to be construed as excluding other of the above forms as identified above.
  • alkyl refers to a straight chain or branched, saturated or unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., “C 1 -C 8 alkyl” refers to an alkyl group having from 1 to 8 carbon atoms). When the number of carbon atoms is not indicated, the alkyl group has from 1 to 8 carbon atoms.
  • C 1 -C 8 alkyl groups include, but are not limited to, methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, —CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH 3 ) 3 ), 1-pentyl (n-pentyl, —CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (n
  • An alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, —O—(C 1 -C 8 alkyl), aryl, —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 —NHC(O)R′, —SO 3 R′, —S(O) 2 R′, —S(O) 2 R′, —S(O)R′, —OH, -halogen, —N 3 , —NH2, —NH(R′), —N(R′) 2 and —CN; where each R′ is independently selected from H, unsubstituted C 1 -C 8 alkyl and aryl.
  • alkenyl refers to a C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, Le., a carbon-carbon, sp 2 double bond. Examples include, but are not limited to: ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ).
  • alkynyl refers to a C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to: acetylenic (—C ⁇ CH) and propargyl (—CH 2 C ⁇ CH).
  • alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylenes include, but are not limited to: methylene (—CH 2 —) 1,2-ethyl (—CH 2 CH 2 —), 1,3-propyl (—CH 2 CH 2 CH 2 —), 1,4-butyl (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • Typical alkenylene radicals include, but are not limited to: 1,2-ethylene (—CH ⁇ CH—).
  • alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from carbon atoms of a parent alkyne.
  • Typical alkynylene radicals include, but are not limited to: acetylene (—C ⁇ C—), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ C—).
  • aryl refers to a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as “Ar”. An aryl group can be unsubstituted or substituted. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, phenyl, naphthalene, anthracene, biphenyl, and the like.
  • An aryl can be substituted with one or more groups including, but not limited to, —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, -halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 and —CN; wherein each R′ is independently selected from H, —C 1 -C 8 alkyl and unsubstituted aryl.
  • arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • heteroarylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl radical.
  • Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl, and the like.
  • the heteroarylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 ring atoms, typically 1 to 3 heteroatoms selected from N, O, P, and S, with the remainder being carbon atoms.
  • the heteroaryl moiety of the heteroarylalkyl group may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms) and 1 to 3 heteroatoms selected from N, O, P, and S, for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • arylene refers to an aryl group which has two covalent bonds and can be in the para, meta, or ortho configurations as shown in the following structures:
  • the phenyl group can be unsubstituted or substituted with up to four groups including, but not limited to, —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -aryl, —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, -halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 and —CN; wherein each R′ is independently selected from H, —C 1 -C 8 alkyl and aryl.
  • substituted alkyl refers to alkyl, aryl, and arylalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
  • Typical substituents include, but are not limited to, —X, —R, —O ⁇ , —OR, —SR, —S ⁇ , —NR 2 , —NR 3 , ⁇ NR, —CX 3 , —CN, —OCN, —SCN, —N ⁇ C ⁇ O, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , NRC( ⁇ O)R, —C( ⁇ O)R, —C( ⁇ O)NR 2 , —SO 3 ⁇ , ⁇ SO 3 H, —S( ⁇ O) 2 R, —OS( ⁇ O) 2 OR, —S( ⁇ O) 2 NR, —S( ⁇ O)R, —OP( ⁇ O)(OR) 2 , —P( ⁇ O)(OR) 2 , —PO ⁇ 3 , —PO 3 H 2 , —C( ⁇ O)R, —C( ⁇ O
  • heteroaryl and “heterocycle” refer to a ring system in which one or more ring atoms is a heteroatom, e.g., nitrogen, oxygen, phosphate and sulfur.
  • the heterocycle radical comprises 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S.
  • a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • Heterocycles are described in Paquette, “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 82:5566 (1960).
  • heterocycles include, by way of example and not limitation, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, bis-
  • carbon-bonded heterocycles are bonded at the following positions: position 2, 3, 4, 5, or 6 of a pyridine; position 3, 4, 5, or 6 of a pyridazine; position 2, 4, 5, or 6 of a pyrimidine; position 2, 3, 5, or 6 of a pyrazine; position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole; position 2, 4, or 5 of an oxazole, imidazole or thiazole; position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole; position 2 or 3 of an aziridine; position 2, 3, or 4 of an azetidine; position 2, 3, 4, 5, 6, 7, or 8 of a quinoline; or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or 1H-indazole; position 2 of a isoindole or isoindoline; position 4 of a morpholine; and position 9 of a carbazole or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.
  • Carbocycle refers to a saturated or unsaturated ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cycloheptyl and cyclooctyl.
  • a “C 3 -C 8 carbocycle” is a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or unsaturated non-aromatic carbocyclic ring.
  • Representative C 3 -C 8 carbocycles include, but are not limited to, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl and -cyclooctadienyl.
  • a C 3 -C 8 carbocycle group can be unsubstituted or substituted with one or more groups including, but not limited to, —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -aryl, —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, -halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 and —CN; where each R′ is independently selected from H, -C 1 -C 8 alkyl and aryl.
  • C 3 -C 8 carbocyclo refers to a C 3 -C 8 carbocycle group defined above wherein one of the carbocycle groups' hydrogen atoms is replaced with a bond.
  • a “C 1 -C 10 alkylene” is a straight chain, saturated hydrocarbon group of the formula —(CH 2 ) 1-10 —.
  • Examples of a C 1 -C 10 alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, ocytylene, nonylene and decalene.
  • C 3 -C 8 heterocycle refers to an aromatic or non-aromatic C 3 -C 8 carbocycle in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
  • C 3 -C 8 heterocycle include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl and tetrazolyl.
  • a C 3 -C 8 heterocycle can be unsubstituted or substituted with up to seven groups including, but not limited to, —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -aryl, —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, -halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 and —CN; wherein each R′ is independently selected from H, —C 1 -C 8 alkyl and aryl.
  • C 3 -C 8 heterocyclo refers to a C 3 -C 8 heterocycle group defined above wherein one of the heterocycle group's hydrogen atoms is replaced with a bond.
  • a C 3 -C 8 heterocyclo can be unsubstituted or substituted with up to six groups including, but not limited to, —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -aryl, —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, -halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 and —CN; wherein each R′ is independently selected from H,
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of a ligand drug conjugate or linker drug conjugate.
  • the conjugates may contain at least one amino group, and accordingly acid addition salts can be formed with the amino group.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′ methylene bis -(2 hydroxy 3 naphthoate)) salts.
  • sulfate citrate, acetate, oxalate, chloride, bromide,
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterion.
  • phrases “pharmaceutically acceptable solvate” or “solvate” refer to an association of one or more solvent molecules and a ligand drug conjugate or linker drug conjugate.
  • solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • Examples of a “patient” or “subject” include, but are not limited to, a human, rat, mouse, guinea pig, monkey, pig, goat, cow, horse, dog, cat, bird and fowl.
  • the patient or subject is a human.
  • treat refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • treating includes any or all of: preventing growth of tumor cells, cancer cells, or of a tumor; preventing replication of tumor cells or cancer cells, lessening of overall tumor burden or decreasing the number of cancerous cells, and ameliorating one or more symptoms associated with the disease.
  • treating includes any or all of: preventing replication of cells associated with an autoimmune disease state including, but not limited to, cells that produce an autoimmune antibody, lessening the autoimmune-antibody burden and ameliorating one or more symptoms of an autoimmune disease.
  • treating includes any or all of: preventing the growth, multiplication or replication of the pathogen that causes the infectious disease and ameliorating one or more symptoms of an infectious disease.
  • MMAE mono-methyl auristatin E (MW 718); MMAF is N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine (MW 731.5); AEVB is auristatin E valeryl benzylhydrazone, acid labile linker through the C-terminus of AE (MW 732); DMSO is dimethylsulfoxide; DMF is N,N dimethylformamide; HPLC is high pressure liquid chromatography, THF is tetrahydrofuran; and Mc-OSu is maleimidocaproyl N-hydroxysuccimidyl ester.
  • the present invention is drawn to a series of drug linker compounds and conjugate compounds containing a Drug compound (-D) and a Linker unit comprising a Glucuronide unit (—W—).
  • the drug-linker compounds are useful as discrete entities, or can be conjugated to Ligands (L, in some embodiments, antibodies).
  • the Linker unit can operate to provide a suitable, targeted release of a Drug compound(s). Additionally, some Linker Units can have multiple attached drugs (e.g., one to four attached drugs can be represented as -LU-(D) 1-4 ).
  • the ligand drug conjugate compounds generally comprise the following formula I:
  • a is 0 or 1, w is 1, and y is 0, 1 or 2. In some embodiments, a is 0 or 1, w is 1, and y is 0 or 1. In some embodiments, a is 0, w is 1, and y is 0. In some embodiments, a is 0 or 1, w is 1, and y is 1. In some embodiments, a is 1, w is 1, and y is 0. In some embodiments, a is 1, w is 1, and y is 1. In some embodiments, a is 1, w is 1, and y is 1. In some embodiments, p is 1 to 10, 1 to 8, 1 to 6, 1 to 4, 6, 4 or 2. Each of these units is described in more detail herein.
  • a “Linker unit” is a bifunctional compound which can be used to link a Drug unit and a Ligand unit to form a Ligand Drug Conjugate compound (also referred to as a Ligand-Linker-Drug conjugate compound), to a Drug unit to form a Linker-Drug unit, or which is useful in the formation of immunoconjugates.
  • the Linker unit has the formula: -A a -W w —Y y —
  • a is 0 or 1
  • w is 1
  • y is 0, 1 or 2.
  • a is 0 or 1
  • w is 1
  • y is 0 or 1.
  • the Glucuronide unit (—W—) links a Stretcher unit to a Spacer unit if the Stretcher and Spacer units are present, links a Stretcher unit to the Drug moiety if the Spacer unit is absent, and links the Ligand unit to the Drug unit if the Stretcher and Spacer units are absent.
  • the Glucuronide unit includes a site that can be cleaved by a ⁇ -glucuronidase enzyme.
  • the Glucuronide unit comprises a sugar moiety (Su) linked via a glycoside bond (—O′—) to a self-immolative group (Z) of the formula: -[Su-O′—Z]— IIa
  • the glycosidic bond (—O′—) is typically a ⁇ -glucuronidase-cleavage site, such as a bond cleavable by human, lysosomal ⁇ -glucuronidase.
  • the term “self-immolative group” refers to a di- or tri-functional chemical moiety that is capable of covalently linking together two or three spaced chemical moieties (Le., the sugar moiety (via a glycosidic bond), a Drug unit (directly or indirectly via a Spacer unit), and, in some embodiments, a Ligand unit (directly or indirectly via a Stretcher unit) into a stable molecule.
  • the self-immolative group will spontaneously separate from the first chemical moiety (e.g., the Spacer or Drug unit) if its bond to the Sugar moiety is cleaved.
  • the Sugar moiety (Su) is cyclic hexose, such as a pyranose, or a cyclic pentose, such as a furanose.
  • the pyranose is a glucuronide or hexose.
  • the Sugar moiety is usually in the ⁇ -D conformation.
  • the pyranose is a ⁇ -D-glucuronide moiety (i.e., ⁇ -D-glucuronic acid linked to the self-immolative group —Z— via a glycosidic bond that is cleavable by ⁇ -glucuronidase).
  • the sugar moiety is unsubstituted (e.g., a naturally occurring cyclic hexose or cyclic pentose).
  • the sugar moiety can be a substituted ⁇ -D-glucuronide (i.e., glucuronic acid substituted with one or more group, such hydrogen, hydroxyl, halogen, sulfur, nitrogen or lower alkyl.
  • the self-immolative group Z is a p-aminobenzyl alcohol (PAB) unit, as further described herein.
  • PAB p-aminobenzyl alcohol
  • Other suitable self immolative groups are known in the art.
  • the Glucuronide unit has one of the following formulae:
  • the glycosidic bond comprises the oxygen bond between Su and the self immolative group Z
  • each R is independently hydrogen, halo (e.g., chloro, bromo, fluoro, etc), —CN, —NO 2 , or other electron withdrawing or donating group, provided that the Glucuronide unit (and Z in particular) undergoes self-immolation upon cleavage of the glycosidic bond.
  • each R is independently hydrogen, halo (e.g., chloro, bromo, fluoro, etc), —CN or —NO 2 .
  • the Glucuronide unit has one of the following formulae:
  • the glycosidic bond (—O′—) comprises the oxygen bond between Su and the self immolative group Z, and each R is independently hydrogen.
  • the self-immolative group (Z) is covalently linked to the Sugar moiety, to the Drug unit (directly or indirectly via the Spacer unit(s)), and to the Ligand unit (directly or indirectly via the Stretcher unit(s)).
  • a Drug Linker conjugate has the following formula:
  • a Ligand Drug conjugate compound e.g., an antibody drug conjugate (ADC)
  • ADC antibody drug conjugate
  • a Ligand Drug conjugate compound comprising the Glucuronide unit has the following formula:
  • a Ligand Drug conjugate compound comprising the Glucuronide unit has the following formula:
  • a Ligand Drug conjugate compound comprising the Glucuronide unit has the following formula:
  • a Ligand Drug conjugate compound comprising the Glucuronide unit has the following formula:
  • the Ligand unit is linked (directly or indirectly) to the Sugar moiety (S), which is linked to the self-immolative group (Z) which is linked (directly or indirectly) to the Drug unit, according to the following formula.
  • the Sugar moiety (Su) can be linked directly to the Ligand unit or indirectly via a Stretcher unit.
  • the self-immolative group (Z) can be linked directly to the Drug unit or indirectly via a Spacer unit.
  • a Drug-Linker compound has the following formula: A a -[Su-O′—Z] W -Y y -D IIo wherein A, a, Su, O′, Z, w, Y, y and D are defined as above. Typically from 1 to 20 of such Drug-Linker compounds can be linked to a Ligand unit.
  • the Stretcher unit (-A-), when present, is capable of linking a Ligand unit to a Glucuronide unit (—W—).
  • a Ligand unit (L) has a functional group that can form a bond with a functional group of a Stretcher.
  • Useful functional groups that can be present on a Ligand unit, either naturally or via chemical manipulation include, but are not limited to, sulfhydryl (—SH), amino, hydroxyl, carboxy, the anomeric hydroxyl group of a carbohydrate, and carboxyl.
  • the Ligand unit functional groups are sulfhydryl and/or amino. Sulfhydryl groups can be generated by reduction of an intramolecular disulfide bond of a Ligand.
  • Sulfhydryl groups also can be generated by reaction of an amino group of a lysine moiety of a Ligand using 2-iminothiolane (Traut's reagent) or another sulfhydryl generating reagent.
  • the Stretcher unit forms a bond with a sulfur atom of the Ligand unit.
  • the sulfur atom can be derived from a sulfhydryl group of a Ligand.
  • Representative Stretcher units of this embodiment are depicted within the square brackets of Formulas IIIa and IIIb, wherein L-, —W—, —Y—, -D, w and y are as defined above, and R 17 is direct bond or selected from —C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8
  • An illustrative Stretcher unit is that of Formula IIIa wherein R 17 is —(CH 2 ) 5 —:
  • Stretcher unit is that of Formula Ilia wherein R 17 is —(CH 2 CH 2 O) r —CH 2 —; and r is 2:
  • Stretcher unit is that of Formula IIIa wherein R 17 is —(CH 2 CH 2 O) r —CH 2 —CH 2 —; and r is 2:
  • Stretcher unit is that of Formula III wherein R 17 is —(CH 2 CH 2 O) r —CH 2 —CH 2 —; and r is 2
  • Still another illustrative Stretcher unit is that of Formula IIIb wherein R 17 is —(CH 2 ) 5 —:
  • the Stretcher unit is linked to the Ligand unit via a disulfide bond between a sulfur atom of the Ligand unit and a sulfur atom of the Stretcher unit.
  • a representative Stretcher unit of this embodiment is depicted within the square brackets of Formula IV, wherein R 17 , L-, —W—, —Y—, -D, w and y are as defined above.
  • the reactive group of the Stretcher contains a reactive site that can form a bond with a primary or secondary amino group of a Ligand.
  • these reactive sites include, but are not limited to, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates and isothiocyanates.
  • Representative Stretcher units of this embodiment are depicted within the square brackets of Formulas Va and Vb, wherein —R 17 —, L-, —W—, —Y—, -D, w and y are as defined above;
  • the reactive group of the Stretcher contains a reactive site that is reactive to a modified carbohydrate (—CHO) group that can be present on a Ligand.
  • a carbohydrate can be mildly oxidized using a reagent such as sodium periodate and the resulting (—CHO) unit of the oxidized carbohydrate can be condensed with a Stretcher that contains a functionality such as a hydrazide, an oxime, a primary or secondary amine, a hydrazine, a thiosemicarbazone, a hydrazine carboxylate, and an arylhydrazide such as those described by Kaneko et. al., 1991, Bioconjugate Chem. 2:133 41.
  • a modified carbohydrate can be prepared by reductive amination.
  • Representative Stretcher units of this embodiment are depicted within the square brackets of Formulas VIa, VIb, and VIc, wherein —R 17 —, L-, —W—, —Y—, -D, w and y are as defined above.
  • the Spacer unit(s) is a self-immolative spacer.
  • self-immolative spacer refers to a bifunctional chemical moiety that is capable of covalently linking together two spaced chemical moieties into a normally stable tripartite molecule. It will spontaneously separate from the second chemical moiety if its bond to the first moiety is cleaved.
  • —Y— is linked to -Ww - via the methylene carbon atom of the self-immolative group, and linked connected directly to -D via a carbonate, carbamate or ether group.
  • Scheme 1 depicts a mechanism of Drug release of a glucuronide-based linker which is attached directly to -D via a carbonate group.
  • —Yy- is a p-aminobenzyl alcohol (PAB) unit (see, e.g., Schemes 1 and 2, infra) whose phenylene portion is substituted with Qm wherein Q is —C1-C8 alkyl, —O—(C1-C8 alkyl), -halogen, -nitro or -cyano; and m is an integer ranging from 0-4.
  • PAB p-aminobenzyl alcohol
  • self-immolative spacers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group such as 2-aminoimidazol-5-methanol derivatives (see, e.g., Hay et. al., 1999, Bioorg. Med. Chem. Lett. 9:2237) and ortho or para-aminobenzylacetals.
  • Spacers can be used that undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (see, e.g., Rodrigues et.
  • the Spacer unit is a branched bis(hydroxymethyl)styrene (BHMS) unit as depicted in the following Scheme, which can be used to incorporate and release multiple drugs.
  • BHMS branched bis(hydroxymethyl)styrene
  • a Ligand unit includes within its scope any molecule that binds or reactively associates or complexes with a receptor, antigen or other receptive moiety associated with a given target-cell or cell population.
  • the Ligand unit acts to deliver a Drug unit (infra) to the particular target cell or cell population with which the Ligand unit reacts.
  • Drug unit infra
  • Such Ligand units include, but are not limited to, large molecular weight proteins such as, for example, full-length antibodies, antibody fragments, smaller molecular weight proteins, polypeptides or peptides, lectins, glycoproteins, non-peptides, vitamins, nutrient-transport molecules, and any other cell binding molecule or substance.
  • Non-immunoreactive proteins, polypeptides, or peptide ligands include, but are not limited to, transferrin, epidermal growth factors (“EGF”), bombesin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, transforming growth factors (“TGF”), such as TGF- ⁇ and TGF- ⁇ , vaccinia growth factor (“VGF”), insulin and insulin-like growth factors I and II, lectins, somatostatin and apoprotein from low density lipoprotein.
  • EGF epidermal growth factors
  • TGF transforming growth factors
  • VGF vaccinia growth factor
  • I and II insulin and insulin-like growth factors I and II
  • lectins somatostatin and apoprotein from low density lipoprotein.
  • Useful polyclonal antibodies are heterogeneous populations of antibody molecules, such as those derived from the sera of immunized animals.
  • Various procedures known in the art may be used for the production of polyclonal antibodies to an antigen-of-interest.
  • various host animals can be immunized by injection with an antigen of interest or derivative thereof, including but not limited to rabbits, mice, rats, and guinea pigs.
  • adjuvants can be used to increase the immunological response, depending on the host species, and including but not limited to Freund's (complete and incomplete) adjuvant, mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum.
  • BCG Bacille Calmette-Guerin
  • corynebacterium parvum Such adjuvants are also well known in the art.
  • Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cell antigen (such as a cancer or autoimmune cell antigen), a viral antigen, a microbial antigen, a protein, a peptide, a carbohydrate, a chemical, a nucleic acid, or antigen-binding fragments thereof.
  • a monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art.
  • Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and IgD and any subclass thereof.
  • the hybridoma producing the mAbs of use in this invention may be cultivated in vitro or in vivo.
  • Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, chimeric monoclonal antibodies and functionally active antibody fragments.
  • Human monoclonal antibodies may be made by any of numerous techniques known in the art (see, e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; Olsson et al., 1982, Meth. Enzymol. 92:3-16; and U.S. Pat. Nos. 5,939,598 and 5,770,429).
  • recombinant antibodies such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are useful antibodies.
  • recombinant antibodies are antibody molecules from non-human species having one or more complementarity determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule.
  • CDRs complementarity determining regions
  • Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87/02671; European Patent Publication No. 0 184 187; European Patent Publication No. 0 171 496; European Patent Publication No. 0 173 494; International Publication No. WO 86/01533; U.S. Pat. No. 4,816,567; European Patent Publication No. 012 023; Berter et al, 1988, Science 240:1041-1043; Liu et a., 1987, Proc. Natl. Acad. Sci.
  • Completely human antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes.
  • the transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention.
  • Monoclonal antibodies directed against the antigen can be obtained using conventional hybridoma technology.
  • the human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies.
  • Completely human antibodies that recognize a selected epitope can be generated using a technique referred to as “guided selection.”
  • a selected non-human monoclonal antibody e.g., a mouse antibody
  • Human antibodies also can be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter, 1991, J. Mol. Biol. 227:381; Marks et al., 1991, J. Mol. Biol.
  • the antibody is monospecific.
  • the antibody can also be a bispecific antibody.
  • Methods for making bispecific antibodies are known in the art. Traditional production of full-length bispecific antibodies is based on the coexpression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (see, e.g., Milstein et al., 1983, Nature 305:537-539). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Similar procedures are disclosed in International Publication No. WO 93/08829, and in Traunecker et al., 1991, EMBO J. 10:3655-3659.
  • antibody variable domains with the desired binding specificities are fused to immunoglobulin constant domain sequences.
  • the fusion typically is with an immunoglobulin heavy chain constant region, comprising at least part of the hinge, C H 2, and C H 3 domains. It is preferred to have the first heavy-chain constant region (C H 1) containing the site necessary for light chain binding, present in at least one of the fusions.
  • Nucleic acids with sequences encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain are inserted into separate expression vectors, and are co-transfected into a suitable host organism.
  • the bispecific antibodies can have a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm.
  • This asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation (International Publication No. WO 94/04690; which is incorporated herein by reference in its entirety).
  • bispecific antibodies can be prepared for use in the treatment or prevention of disease as defined herein.
  • bifunctional antibodies are also described in European Patent Publication No. 0 105 360.
  • hybrid or bifunctional antibodies can be derived either biologically, e.g., by cell fusion techniques, or chemically, especially with cross-linking agents or disulfide-bridge forming reagents, and may comprise whole antibodies or fragments thereof. Methods for obtaining such hybrid antibodies are disclosed for example, in International Publication WO 83/03679, and European Patent Publication No. 0 217 577, both of which are incorporated herein by reference.
  • the antibody also can be a functionally active fragment, derivative or analog of an antibody that immunospecifically binds to a desired target antigen (e.g., a cancer cell antigen, a viral antigen, or a microbial antigen) or other antibodies bound to a target cell(s) or matrix.
  • a desired target antigen e.g., a cancer cell antigen, a viral antigen, or a microbial antigen
  • “functionally active” means that the fragment, derivative or analog is able to elicit anti-anti-idiotype antibodies that recognize the same antigen that the antibody from which the fragment, derivative or analog is derived recognized.
  • the antigenicity of the idiotype of the immunoglobulin molecule can be enhanced by deletion of framework and CDR sequences that are C-terminal to the CDR sequence that specifically recognizes the antigen.
  • synthetic peptides containing the CDR sequences can be used in binding assays with the antigen by any binding assay method known in the art (e.g., the BIAcore assay) (see, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest , Fifth Edition, National Institute of Health, Bethesda, Md.; Kabat et al., 1980, J. Immunology 125(3):961-969).
  • antibodies include fragments of antibodies such as, but not limited to, F(ab′) 2 fragments, Fab′ fragments, Fab fragments, Fvs, single chain antibodies (SCAs) (e.g., as described in U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423-42; Huston et al., 1988, Proc. Natl. Acad. Sci.
  • SCAs single chain antibodies
  • the antibody is a fusion protein of an antibody, or a functionally active fragment thereof, for example in which the antibody is fused via a covalent bond (e.g., a peptide bond), at either the N-terminus or the C-terminus to an amino acid sequence of another protein (or portion thereof, typically at least a 10, 20 or 50 amino acid portion of the protein) that is not the antibody.
  • a covalent bond e.g., a peptide bond
  • the antibody or fragment thereof can be covalently linked to the other protein at the N-terminus of the constant domain.
  • Antibodies can also include analogs and derivatives that are either modified, e.g., by the covalent attachment of any type of molecule as long as such covalent attachment permits the antibody to retain its antigen binding immunospecificity.
  • the derivatives and analogs of the antibodies include those that have been further modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular antibody unit or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of tunicamycin, or the like. Additionally, the analog or derivative can contain one or more unnatural amino acids.
  • amino acid sequence variants of the antibodies are prepared by introducing appropriate nucleotide changes into the antibody nucleic acid, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution is made to arrive at the final construct, provided that the final construct possesses the desired characteristics.
  • the amino acid changes also may alter post-translational processes of the antibody, such as changing the number or position of glycosylation sites.
  • a useful method for identification of certain residues or regions of the antibody that are favored locations for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989, Science 244:1081-1085).
  • a residue or group of target residues are identified (e.g., charged residues such as arg, asp, his, lys, and glu) and replaced by a neutral or negatively charged amino acid (typically alanine or polyalanine) to affect the interaction of the amino acids with antigen.
  • Those amino acid locations demonstrating functional sensitivity to the substitutions then are refined by introducing further or other variants at, or for, the sites of substitution.
  • the site for introducing an amino acid sequence variation is predetermined, the nature of the mutation per se need not be predetermined. For example, to analyze the performance of a mutation at a given site, alanine scanning or random mutagenesis is conducted at the target codon or region and the expressed antibody variants are screened for the desired activity.
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • terminal insertions include an antibody with an N-terminal methionyl residue or the antibody fused to a cytotoxic polypeptide.
  • variants are an amino acid substitution variant. These variants have at least one amino acid residue in the antibody molecule replaced by a different residue.
  • the sites of greatest interest for substitutional mutagenesis include the hypervariable regions, but framework region alterations are also contemplated.
  • Substantial modifications in the biological properties of the antibody are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
  • Naturally-occurring residues are divided into groups based on common side-chain properties:
  • a particularly type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody).
  • a parent antibody e.g., a humanized or human antibody
  • the resulting variant(s) selected for further development will have improved biological properties relative to the parent antibody from which they are generated.
  • a convenient way for generating such substitutional variants involves affinity maturation using phage display. Briefly, several hypervariable region sites (e.g., 6-7 sites) are mutated to generate all possible amino substitutions at each site.
  • the antibody variants thus generated are displayed in a monovalent fashion from filamentous phage particles as fusions to the gene III product of M13 packaged within each particle. The phage-displayed variants are then screened for their biological activity (e.g., binding affinity).
  • alanine scanning mutagenesis can be performed to identify hypervariable region residues contributing significantly to antigen binding.
  • ADCC antigen-dependent cell-mediated cyotoxicity
  • CDC complement dependent cytotoxicity
  • This may be achieved by introducing one or more amino acid substitutions in an Fc region of the antibody.
  • cysteine residue(s) may be introduced in the Fc region, thereby allowing interchain disulfide bond formation in this region.
  • the homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See, e.g., Caron et al., 1992, J. Exp Med.
  • Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al., 1993, Cancer Research 53:2560-2565.
  • an antibody can be engineered which has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities. See, e.g., Stevenson et al., 1989, Anti - Cancer Drug Design 3:219-230.
  • a salvage receptor binding epitope refers to an epitope of the Fc region of an IgG molecule (e.g., IgG 1 , IgG 2 , IgG 3 , or IgG 4 ) that is responsible for increasing the in vivo serum half-life of the IgG molecule.
  • Antibodies may be glycosylated at conserved positions in their constant regions (see, e.g., Jefferis and Lund, 1997, Chem. Immunol. 65:111-128; Wright and Morrison, 1997, TibTECH 15:26-32).
  • the oligosaccharide side chains of the immunoglobulins affect the protein's function (see, e.g., Boyd et al., 1996, Mol. Immunol, 32:1311-1318; Wittwe and Howard, 1990, Biochem.
  • Oligosaccharides may also serve to target a given glycoprotein to certain molecules based upon specific recognition structures.
  • CAMPATH-1H a recombinant humanized murine monoclonal IgG1 antibody which recognizes the CDw52 antigen of human lymphocytes
  • CHO Chinese Hamster Ovary
  • CHO cells with tetracycline-regulated expression of ⁇ (1,4)-N-acetylglucosaminyltransferase III (GnTIII), a glycosyltransferase catalyzing formation of bisecting GIcNAc, was reported to have improved ADCC activity (see, e.g., Umana et al., 1999, Mature Biotech. 17:176-180).
  • N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue.
  • the tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain.
  • X is any amino acid except proline
  • O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.
  • Glycosylation variants of antibodies are variants in which the glycosylation pattern of an antibody is altered.
  • altering is meant deleting one or more carbohydrate moieties found in the antibody, adding one or more carbohydrate moieties to the antibody, changing the composition of glycosylation (glycosylation pattern), the extent of glycosylation, or the like.
  • glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites).
  • the alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).
  • removal of glycosylation sites can be accomplished by amino acid alteration within the native glycosylation sites of the antibody.
  • the amino acid sequence is usually altered by altering the underlying nucleic acid sequence.
  • These methods include, but are not limited to, isolation from a natural source (in the case of naturally-occurring amino acid sequence variants) or preparation by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the antibody.
  • glycosylation may also be altered without altering the amino acid sequence or the underlying nucleotide sequence. Glycosylation largely depends on the host cell used to express the antibody. Since the cell type used for expression of recombinant glycoproteins, e.g., antibodies, as potential therapeutics is rarely the native cell, significant variations in the glycosylation pattern of the antibodies can be expected. See, e.g., Hse et al., 1997, J. Biol. Chem. 272:9062-9070. In addition to the choice of host cells, factors which affect glycosylation during recombinant production of antibodies include growth mode, media formulation, culture density, oxygenation, pH, purification schemes and the like.
  • glycosylation pattern achieved in a particular host organism including introducing or overexpressing certain enzymes involved in oligosaccharide production (see, e.g., U.S. Pat. Nos. 5,047,335; 5,510,261; and 5,278,299).
  • Glycosylation, or certain types of glycosylation can be enzymatically removed from the glycoprotein, for example using endoglycosidase H (Endo H).
  • the recombinant host cell can be genetically engineered, e.g., make defective in processing certain types of polysaccharides.
  • glycosylation structure of antibodies can be readily analyzed by conventional techniques of carbohydrate analysis, including lectin chromatography, NMR, mass spectrometry, HPLC, GPC, monosaccharide compositional analysis, sequential enzymatic digestion, and HPAEC-PAD, which uses high pH anion exchange chromatography to separate oligosaccharides based on charge.
  • Methods for releasing oligosaccharides for analytical purposes include, without limitation, enzymatic treatment (commonly performed using peptide-N-glycosidase F/endo- ⁇ -galactosidase), elimination using harsh alkaline environment to release mainly O-linked structures, and chemical methods using anhydrous hydrazine to release both N- and O-linked oligosaccharides.
  • antibodies also can have modifications (e.g., substitutions, deletions or additions) in amino acid residues that interact with Fc receptors.
  • antibodies include antibodies having modifications in amino acid residues identified as involved in the interaction between the anti-Fc domain and the FcRn receptor (see, e.g., International Publication No. WO 97/34631, which is incorporated herein by reference in its entirety).
  • Antibodies immunospecific for a cancer cell antigen can be obtained commercially, for example, from commercial companies or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques.
  • the nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen can be obtained, e.g., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing.
  • antibodies for the treatment or prevention of cancer can be used.
  • Antibodies immunospecific for a cancer cell antigen can be obtained commercially or produced by any method known to one of skill in the art such as, erg., recombinant expression techniques.
  • the nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen can be obtained, e.g., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing.
  • any target protein can be targeted by an antibody, including any target protein which expression is correlated with expression on cells of a cancer, cell proliferative disorder or tumor.
  • the antigen is a tumor-associated antigen, such as a polypeptide, protein or other molecule that is specifically expressed on the surface of one or more particular type(s) of cancer cell as compared to on one or more normal non-cancerous cell(s).
  • tumor-associated antigens are more abundantly expressed on the surface of the cancer cells as compared to on the surface of the non-cancerous cells. The identification of such tumor-associated cell surface antigens has given rise to the ability to specifically target cancer cells for destruction via antibody-based therapies.
  • Suitable target proteins include human tumor antigens recognized by T cells (Robbins and Kawakami, 1996, Curr. Opin. Immunol 8:628-636, incorporated herein by reference in its entirety), melanocyte lineage proteins, including gp100, MART-1/MelanA, TRP-1 (gp75), tyrosinase; Tumor-specific widely shared antigens, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-1, N-acetylglucosaminyltransferase-V, p15; Tumor-specific mutated antigens, beta-catenin, MUM-1, CDK4; Nonmelanoma antigens for breast, ovarian, cervical and pancreatic carcinoma, HER-2/neu, human papillomavirus-E6, -E7, MUC-1; cancer antigens, such as KS 1/4 pan-carcinoma antigen (Perez and Walker, 1990, J.
  • melanocyte lineage proteins including
  • melanoma antigen gp75 (Vijayasardahl et al., 1990, J. Exp. Med. 171(4):1375-1380); high molecular weight melanoma antigen (HMW-MM) (Natali et al., 1987, Cancer 59:55-63; Mittelman et al., 1990, J. Clin. Invest 86:2136-2144); prostate specific membrane antigen; carcinoembryonic antigen (CEA) (Foon et al., 1994, Proc. Am. Soc. Clin. Oncol.
  • CEA carcinoembryonic antigen
  • ganglioside GM2 Livingston et al., 1994, J. Clin. Oncol. 12:1036-1044
  • ganglioside GM3 Hoon et al., 1993, Cancer Res. 53:5244-5250
  • tumor-specific transplantation type of cell-surface antigen TSTA
  • virally-induced tumor antigens including T-antigen DNA tumor viruses and envelope antigens of RNA tumor viruses
  • oncofetal antigen-alpha-fetoprotein such as CEA of colon, bladder tumor oncofetal antigen
  • differentiation antigen such as human lung carcinoma antigen L6, L20 (Hellstrom et al., 1986, Cancer Res. 46:3917-3923); antigens of fibrosarcoma, human leukemia T cell antigen-Gp37 (Bhattacharya-Chatterjee et al., 1988, J. Immunol. 141:1398-1403); neoglycoprotein, sphingolipids, breast cancer antigen such as EGFR (Epidermal growth factor receptor), HER2 antigen (p185HER2), polymorphic epithelial mucin (PEM) (Hilkens et al., 1992, Trends in Bio. Chem. Sci.
  • differentiation antigen such as human lung carcinoma antigen L6, L20 (Hellstrom et al., 1986, Cancer Res. 46:3917-3923); antigens of fibrosarcoma, human leukemia T cell antigen-Gp37 (Bhattacharya-Chatterjee et al.,
  • the antibody is useful for the treatment of cancer.
  • antibodies available for the treatment of cancer include, but are not limited to R ITUXAN ® (rituximab; Genentech) which is a chimeric anti-CD20 monoclonal antibody for the treatment of patients with non-Hodgkin's lymphoma; OVAREX (AltaRex Corporation, Mass.) which is a murine antibody for the treatment of ovarian cancer; PANOREX (Glaxo Wellcome, NC) which is a murine IgG 2a antibody for the treatment of colorectal cancer; CETUXIMAB ERBITUX (Imclone Systems Inc., NY) which is an anti-EGFR IgG chimeric antibody for the treatment of epidermal growth factor positive cancers, such as head and neck cancer; VITAXIN (Medimmune, Inc., MD) which is a humanized antibody for the treatment of sarcoma; CAMPATH I/H (Leukosite, Mass
  • the antibody is an antibody against the following antigens (where exemplary cancers are indicated in parentheses): CA125 (ovarian), CA15-3 (carcinomas), CA19-9 (carcinomas), L6 (carcinomas), Lewis Y (carcinomas), Lewis X (carcinomas), alpha fetoprotein (carcinomas), CA 242 (colorectal), placental alkaline phosphatase (carcinomas), prostate specific membrane antigen (prostate), EphB2, TMEFF2, prostatic acid phosphatase (prostate), epidermal growth factor (carcinomas), MAGE-1 (carcinomas), MAGE-2 (carcinomas), MAGE-3 (carcinomas), MAGE-4 (carcinomas), anti-transferrin receptor (carcinomas), p97 (melanoma), MUC1-KLH (breast cancer), CEA (colorectal), gp100 (melanoma), MART1 (melanoma), prostate specific antigen (prostate), IL-2 receptor
  • Some specific, useful antibodies include, but are not limited to, BR96 mAb (Trail et. al., 1993, Science 261:212-215), BR64 (Trail et al., 1997, Cancer Research 57:100-105), mAbs against the CD40 antigen, such as S2C6 mAb (Francisco et al., 2000, Cancer Res. 60:3225-3231) or other anti-CD40 antibodies, such as those disclosed in U.S Patent Publication Nos.
  • mAbs against the CD70 antigen such as 1F6 mAb and 2F2 mAb
  • mAbs against the CD30 antigen such as AC10 (Bowen et al., 1993, J. Immunol. 151:5896-5906; Wahl et al., 2002, Cancer Res. 62(13):3736-42) or MDX-0060 (U.S. Patent Publication No. 2004-0006215).
  • Other internalizing antibodies that bind to tumor associated antigens can be used and have been reviewed (Franke et al., 2000, Cancer Biother. Radiopharm. 15:459 76; Murray, 2000, Semin. Oncol. 27:64 70; Breitling, F., and Dubel, S., Recombinant Antibodies, John Wiley, and Sons, New York, 1998).
  • antibodies for the treatment or prevention of an autoimmune disease are used.
  • Antibodies immunospecific for an antigen of a cell that is responsible for producing autoimmune antibodies can be obtained from any organization (e.g., a university scientist or a company) or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques.
  • Useful antibodies are immunospecific for the treatment of autoimmune diseases include, but are not limited to, anti-nuclear antibody; anti-ds DNA antibody; anti-ss DNA antibody; anti-cardiolipin antibody IgM, IgG; anti-phospholipid antibody IgM, IgG; anti-SM antibody; anti-mitochondrial antibody; anti-thyroid antibody; anti-microsomal antibody; anti-thyroglobulin antibody; anti-SCL-70 antibody; anti-Jo antibody; anti-U 1 RNP antibody; anti-La/SSB antibody; anti-SSA antibody; anti-SSB antibody; anti-perital cells antibody; anti-histone antibody; anti-RNP antibody; anti-C-ANCA antibody; anti-P-ANCA antibody; anti-centromere antibody; anti-Fibrillarin antibody, and anti-GBM antibody.
  • useful antibodies can bind to a receptor or a receptor complex expressed on a target cell.
  • the receptor or receptor complex can comprise an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein.
  • suitable immunoglobulin superfamily members are CD2, CD3, CD4, CD8, CD19, CD22, CD28, CD79, CD90, CD152/CTLA-4, PD-1, and ICOS.
  • TNF receptor superfamily members are CD27, CD40, CD95/Fas, CD134/OX40, CD137/4-1BB, TNF-R1, TNFR-2, RANK, TACI, BCMA, osteoprotegerin, Apo2/TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, and APO-3.
  • suitable integrins are CD11a, CD11b, CD11c, CD18, CD29, CD41, CD49a, CD49b, CD49c, CD49d, CD49e, CD49f, CD103, and CD104.
  • suitable lectins are C-type, S-type, and I-type lectin.
  • the ligand binds to an activated lymphocyte that is associated with an autoimmune disease.
  • useful ligands immunospecific for a viral or a microbial antigen are monoclonal antibodies.
  • viral antigen includes, but is not limited to, any viral peptide, polypeptide protein (e.g., HIV gp120, HIV nef, RSV F glycoprotein, influenza virus neuraminidase, influenza virus hemagglutinin, HTLV tax, herpes simplex virus glycoprotein (e.g., gB, gC, gD, and gE) and hepatitis B surface antigen) that is capable of eliciting an immune response.
  • polypeptide protein e.g., HIV gp120, HIV nef, RSV F glycoprotein, influenza virus neuraminidase, influenza virus hemagglutinin, HTLV tax, herpes simplex virus glycoprotein (e.g., gB, gC, gD, and gE) and hepatitis B surface antigen
  • microbial antigen includes, but is not limited to, any microbial peptide, polypeptide, protein, saccharide, polysaccharide, or lipid molecule (e.g., a bacterial, fungi, pathogenic protozoa, or yeast polypeptide including, e.g., LPS and capsular polysaccharide 5/8) that is capable of eliciting an immune response.
  • microbial antigen includes, but is not limited to, any microbial peptide, polypeptide, protein, saccharide, polysaccharide, or lipid molecule (e.g., a bacterial, fungi, pathogenic protozoa, or yeast polypeptide including, e.g., LPS and capsular polysaccharide 5/8) that is capable of eliciting an immune response.
  • Antibodies immunospecific for a viral or microbial antigen can be obtained commercially or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques.
  • the nucleotide sequence encoding antibodies that are immunospecific for a viral or microbial antigen can be obtained, e.g., from the GenBank database or a database like it, literature publications, or by routine cloning and sequencing.
  • useful ligands are those that are useful for the treatment or prevention of viral or microbial infection in accordance with the methods disclosed herein.
  • antibodies available useful for the treatment of viral infection or microbial infection include, but are not limited to, SYNAGIS (Medimmune, Inc., MD) which is a humanized anti-respiratory syncytial virus (RSV) monoclonal antibody useful for the treatment of patients with RSV infection; PRO542 (Progenics) which is a CD4 fusion antibody useful for the treatment of HIV infection; OSTAVIR (Protein Design Labs, Inc., CA) which is a human antibody useful for the treatment of hepatitis B virus; PROTOVIR (Protein Design Labs, Inc., CA) which is a humanized IgG 1 antibody useful for the treatment of cytomegalovirus (CMV); and anti-LPS antibodies.
  • SYNAGIS Medimmune, Inc., MD
  • RSV humanized anti-respiratory syncytial
  • antibodies useful in the treatment of infectious diseases include, but are not limited to, antibodies against the antigens from pathogenic strains of bacteria (e.g., Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria gonorrheae, Neisseria meningitidis, Corynebacterium diphtheriae, Clostridium botulinum, Clostridium perfringens, Clostridium tetani, Hemophilus influenzae, Klebsiella pneumoniae, Klebsiella ozaenas, Klebsiella rhinoscleromotis, Staphylococc aureus, Vibrio colerae, Escherichia coli, Pseudomonas aeruginosa, Campylobacter (Vibrio) fetus, Aeromonas hydrophila, Bacillus cereus, Edwardsiella tarda, Yersinia enterocolitica, Yersinia
  • antibodies useful in this invention for treatment of viral disease include, but are not limited to, antibodies against antigens of pathogenic viruses, such as for example: Poxviridae, Herpesviridae, Herpes Simplex virus 1, Herpes Simplex virus 2, Adenoviridae, Papovaviridae, Enteroviridae, Picornaviridae, Parvoviridae, Reoviridae, Retroviridae, influenza viruses, parainfluenza viruses, mumps, measles, respiratory syncytial virus, rubella, Arboviridae, Rhabdoviridae, Arenaviridae, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis E virus, Non-A/Non-B Hepatitis virus, Rhinoviridae, Coronaviridae, Rotoviridae, and Human Immunodeficiency Virus.
  • pathogenic viruses such as for example: Poxviridae, Herpesvirida
  • the Drug unit can be any cytotoxic, cytostatic or immunomodulatory drug.
  • the Drug unit D has a nitrogen atom that can form a bond with the Spacer unit.
  • drug unit and “Drug moiety” are synonymous and used interchangeably.
  • cytotoxic or immunomodulatory agents include, for example, antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cis-platin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, calmodulin inhibitors, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, maytansinoids, nitrosoureas, platinols, pore-forming compounds, purine antimetabolites, puromycins, radiation sensitizers, rapamycins, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, or the like.
  • alkylating agents e.g., platinum complexes such as c
  • cytotoxic or immunomodulatory agents include, for example, an androgen, anthramycin (AMC), asparaginase, 5-azacytidine, azathioprine, bleomycin, busulfan, buthionine sulfoximine, calicheamicin, calicheamicin derivatives, camptothecin, carboplatin, carmustine (BSNU), CC-1065, chlorambucil, cisplatin, colchicine, cyclophosphamide, cytarabine, cytidine arabinoside, cytochalasin B, dacarbazine, dactinomycin (formerly actinomycin), daunorubicin, decarbazine, DM1, DM4, docetaxel, doxorubicin, etoposide, an estrogen, 5-fluordeoxyuridine, 5-fluorouracil, gemcitabine, gramicidin D, hydroxyurea, idarubicin, if
  • suitable cytotoxic agents include, for example, DNA minor groove binders (e.g., enediynes and lexitropsins, a CBI compound; see also U.S. Pat. No. 6,130,237), duocarmycins, taxanes (e.g., paclitaxel and docetaxel), puromycins, vinca alkaloids, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, echinomycin, combretastatin, netropsin, epothilone A and B, estramustine, cryptophycins, cemadotin, maytansinoids, discodermolide, eleutherobin, and mitoxantrone.
  • DNA minor groove binders e.g., enediynes and lexitropsins, a CBI compound; see also U.S. Pat
  • the Drug is an anti-tubulin agent.
  • anti-tubulin agents include, but are not limited to, taxanes (e.g., Taxol® (paclitaxel), Taxotere® (docetaxel)), T67 (Tularik) and vinca alkyloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine).
  • antitubulin agents include, for example, baccatin derivatives, taxane analogs, epothilones (e.g., epothilone A and B), nocodazole, colchicine and colcimid, estramustine, cryptophycins, cemadotin, maytansinoids, combretastatins, discodermolide, and eleutherobin.
  • the cytotoxic agent is a maytansinoid, another group of anti-tubulin agents.
  • the maytansinoid can be maytansine or DM-1 (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res. 52:127-131).
  • the Drug is an auristatin, such as auristatin E or a derivative thereof.
  • the auristatin E derivative can be an ester formed between auristatin E and a keto acid.
  • auristatin E can be reacted with paraacetyl benzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively.
  • Other typical auristatin derivatives include AFP, MMAF, and MMAE.
  • the synthesis and structure of auristatin derivatives are described in U.S. Patent Application Publication Nos. 2003-0083263, 2005-0238649 and 2005-0009751; International Patent Publication No. WO 04/010957, International Patent Publication No.
  • -D is either formula D E or D F :
  • R 3 , R 4 and R 7 are independently isopropyl or sec-butyl and R 5 is —H. In an exemplary embodiment, R 3 and R 4 are each isopropyl, R 5 is H, and R 7 is sec-butyl.
  • R 2 and R 6 are each methyl, and R 9 is H.
  • each occurrence of R 8 is —OCH 3 .
  • R 3 and R 4 are each isopropyl
  • R 2 and R 6 are each methyl
  • R 5 is H
  • R 7 is sec-butyl
  • each occurrence of R 8 is —OCH 3
  • R 9 is H.
  • Z is —O— or —NH—.
  • R 10 is aryl
  • R 10 is -phenyl
  • R 11 is H, methyl or t-butyl.
  • R 11 is —CH(R 15 ) 2 , wherein R 15 is —(CH 2 ) n —N(R 16 ) 2 , and R 16 is —C 1 -C 8 alkyl or —(CH 2 ) n —COOH.
  • R 11 is —CH(R 15 ) 2 , wherein R 15 is —(CH 2 ) n —SO 3 H.
  • Illustrative Drug units (-D) include the drug units having the following structures:
  • hydrophilic groups such as but not limited to triethylene glycol esters (TEG), as shown above, can be attached to the Drug Unit at R 11 .
  • TEG triethylene glycol esters
  • the hydrophilic groups assist in the internalization and non-agglomeration of the Drug Unit.
  • the Drug unit is an amino-benzoic acid derivative of an auristatin of the following formula:
  • the Drug unit is of the following formula:
  • the Drug unit is of the following formula:
  • the Drug unit is of the following formula:
  • the Drug unit is of the following formula:
  • the Drug unit is not a radioisotope. In some embodiments, the Drug unit is not radioactive.
  • the Drug unit is an antimetabolite.
  • the antimetabolite can be, for example, a purine antagonist (e.g., azothioprine or mycophenolate mofetil), a dihydrofolate reductase inhibitor (e.g., methotrexate), acyclovir, gangcyclovir, zidovudine, vidarabine, ribavarin, azidothymidine, cytidine arabinoside, amantadine, dideoxyuridine, iododeoxyuridine, poscarnet, or trifluridine.
  • a purine antagonist e.g., azothioprine or mycophenolate mofetil
  • a dihydrofolate reductase inhibitor e.g., methotrexate
  • acyclovir gangcyclovir
  • zidovudine vidarabine
  • ribavarin azidothymidine
  • the Drug unit is tacrolimus, cyclosporine, FU506 or rapamycin.
  • the Drug is aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, bexarotene, bexarotene, calusterone, capecitabine, celecoxib, cladribine, Darbepoetin alfa, Denileukin diftitox, dexrazoxane, dromostanolone propionate, epirubicin, Epoetin alfa, estramustine, exemestane, Filgrastim, floxuridine, fludarabine, fulvestrant, gemcitabine, gemtuzumab ozogamicin (MYLOTARG), goserelin, idarubicin, ifosfamide, im
  • the Drug moiety is an immunomodulatory agent.
  • the immunomodulatory agent can be, for example, gangcyclovir, etanercept, tacrolimus, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolate mofetil or methotrexate.
  • the immunomodulatory agent can be, for example, a glucocorticoid (e.g., cortisol or aidosterone) or a glucocorticoid analogue (e.g., prednisone or dexamethasone).
  • the immunomodulatory agent is an anti-inflammatory agent, such as arylcarboxylic derivatives, pyrazole-containing derivatives, oxicam derivatives and nicotinic acid derivatives.
  • Classes of anti-inflammatory agents include, for example, cyclooxygenase inhibitors, 5-lipoxygenase inhibitors, and leukotriene receptor antagonists.
  • Suitable cyclooxygenase inhibitors include meclofenamic acid, mefenamic acid, carprofen, diclofenac, diflunisal, fenbufen, fenoprofen, indomethacin, ketoprofen, nabumetone, sulindac, tenoxicam and tolmetin.
  • Suitable lipoxygenase inhibitors include redox inhibitors (e.g., catechol butane derivatives, nordihydroguaiaretic acid (NDGA), masoprocol, phenidone, lanopalen, indazolinones, naphazatrom, benzofuranol, alkylhydroxylamine), and non-redox inhibitors (e.g., hydroxythiazoles, methoxyalkylthiazoles, benzopyrans and derivatives thereof, methoxytetrahydropyran, boswellic acids and acetylated derivatives of boswellic acids, and quinolinemethoxyphenylacetic acids substituted with cycloalkyl radicals), and precursors of redox inhibitors.
  • redox inhibitors e.g., catechol butane derivatives, nordihydroguaiaretic acid (NDGA), masoprocol, phenidone, lanopalen, indazolinones,
  • lipoxygenase inhibitors include antioxidants (e.g., phenols, propyl gallate, flavonoids and/or naturally occurring substrates containing flavonoids, hydroxylated derivatives of the flavones, flavonol, dihydroquercetin, luteolin, galangin, orobol, derivatives of chalcone, 4,2′,4′-trihydroxychalcone, ortho-aminophenols, N-hydroxyureas, benzofuranols, ebselen and species that increase the activity of the reducing selenoenzymes), iron chelating agents (e.g., hydroxamic acids and derivatives thereof, N-hydroxyureas, 2-benzyl-1-naphthol, catechols, hydroxylamines, carnosol trolox C, catechol, naphthol, sulfasalazine, zyleuton, 5-hydroxyanthranilic acid and 4-(omega-arylalkyl
  • lipoxygenase inhibitors include inhibitors of eicosanoids (e.g., octadecatetraenoic, eicosatetraenoic, docosapentaenoic, eicosahexaenoic and docosahexaenoic acids and esters thereof, PGE1 (prostaglandin E1), PGA2 (prostaglandin A2), viprostol, 15-monohydroxyeicosatetraenoic, 15-monohydroxy-eicosatrienoic and 15-monohydroxyeicosapentaenoic acids, and leukotrienes B5, C5 and D5), compounds interfering with calcium flows, phenothiazines, diphenylbutylamines, verapamil, fuscoside, curcumin, chlorogenic acid, caffeic acid, 5,8,11,14-eicosatetrayenoic acid (ETYA), hydroxyphenylretinamide,
  • Leukotriene receptor antagonists include calcitriol, ontazolast, Bayer Bay-x-1005, Ciba-Geigy CGS-25019C, ebselen, Leo Denmark ETH-615, Lilly LY-293111, Ono ONO-4057, Terumo TMK-688, Boehringer Ingleheim BI-RM-270, Lilly LY 213024, Lilly LY 264086, Lilly LY 292728, Ono ONO LB457, Pfizer 105696, Perdue Frederick PF 10042, Rhone-Poulenc Rorer RP 66153, SmithKline Beecham SB-201146, SmithKline Beecham SB-201993, SmithKline Beecham SB-209247, Searle SC-53228, Sumitamo SM 15178, American Home Products WAY 121006, Bayer Bay-o-8276, Warner-Lambert CI-987, Warner-Lambert CI-987BPC-15LY 223982, Lilly
  • a Glucuronide unit and glucuronide-based Linker-Drug conjugate can be synthesized by any suitable technique.
  • the synthesis of Glucuronide-based prodrugs is disclosed in, for example, Desbene et al., 1998, Anticancer Drug Des. 13:955-68.
  • a Ligand Drug compound conjugate comprising a glucuronide-based Linker-Drug conjugate can be synthesized by techniques in the art.
  • a glucuronide-based Linker-Drug conjugate can comprise an acetamide functionality for conjugation to a Ligand unit.
  • a ⁇ -glucuronide prodrug of doxorubicin (3) is shown in Scheme 1.
  • the amide can be modified, via the amine precursor, to possess a reactive group such as a bromoacetamide or maleimide for attachment to a Ligand, such as an antibody.
  • Scheme 2 discloses exemplary antibody drug conjugates of MMAE, and MMAF and another potent doxorubicin derivative; doxorubicin propyl oxazoline (DPO; 2) which is a precursor to 2-pyrrolinodoxorubicin (4) as shown in Scheme 2. Additionally, shown in Scheme 2a is a ⁇ -glucuronide prodrug of MMAE.
  • DPO doxorubicin propyl oxazoline
  • Scheme 2a is a ⁇ -glucuronide prodrug of MMAE.
  • the glucuronide-based Linker-Drug conjugate can be, for example, bromoacetamide-glucuronide-MMAE; bromoacetamide-glucuronide-MMAF; glucuronide-staurosporine; or glucuronide-amino CBI minor groove binder (SN26597), as shown in the following formula.
  • compositions can be in any form that allows for the composition to be administered to a patient.
  • the composition can be in the form of a solid, liquid or gas (aerosol).
  • routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, intra-tumor, and intranasal.
  • Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compositions are administered parenterally.
  • the compounds are administered intravenously.
  • a Ligand Drug conjugate compound is administered in the absence of an administration of a beta-glucuronidase.
  • compositions can be formulated so as to allow a compound to be bioavailable upon administration of the composition to a patient.
  • Compositions can take the form of one or more dosage units, where for example, a tablet can be a single dosage unit, and a container of a compound in aerosol form can hold a plurality of dosage units.
  • compositions can be non-toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of animal (e.g., human), the particular form of the compound, the manner of administration, and the composition employed.
  • the pharmaceutically acceptable carrier or vehicle can be particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) can be liquid, with the compositions being, for example, an oral syrup or injectable liquid.
  • the carrier(s) can be gaseous or particulate, so as to provide an aerosol composition useful in, e.g., inhalatory administration.
  • composition When intended for oral administration, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition typically contains one or more inert diluents.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.
  • composition when in the form of a capsule, e.g., a gelatin capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.
  • a liquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.
  • the composition can be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension.
  • the liquid can be useful for oral administration or for delivery by injection.
  • a composition can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.
  • the liquid compositions can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride
  • fixed oils such as synthetic mono or digylcer
  • a parenteral composition can be enclosed in ampoule, a disposable syringe or a multiple-dose vial made of glass, plastic or other material.
  • Physiological saline is an exemplary adjuvant.
  • An injectable composition is preferably sterile.
  • the amount of the compound that is effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • compositions comprise an effective amount of a compound such that a suitable dosage will be obtained. Typically, this amount is at least about 0.01% of a compound by weight of the composition. When intended for oral administration, this amount can be varied to range from about 0.1% to about 80% by weight of the composition. In one aspect, oral compositions can comprise from about 4% to about 50% of the compound by weight of the composition. In yet another aspect, present compositions are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of the compound.
  • the composition can comprise from about 0.01 to about 100 mg of a compound per kg of the animal's body weight. In one aspect, the composition can include from about 1 to about 100 mg of a compound per kg of the animal's body weight. In another aspect, the amount administered will be in the range from about 0.1 to about 25 mg/kg of body weight of a compound.
  • the dosage of a compound administered to a patient is typically about 0.01 mg/kg to about 2000 mg/kg of the animal's body weight. In some embodiments, the dosage administered to a patient is between about 0.01 mg/kg to about 10 mg/kg of the animal's body weight. In some embodiments, the dosage administered to a patient is between about 0.1 mg/kg and about 250 mg/kg of the animal's body weight. In some embodiments, the dosage administered to a patient is between about 0.1 mg/kg and about 20 mg/kg of the animal's body weight. In some embodiments, the dosage administered is between about 0.1 mg/kg to about 10 mg/kg of the animal's body weight. In some embodiments, the dosage administered is between about 1 mg/kg to about 15 mg/kg of the animal's body weight. In some embodiments, the dosage administered is between about 1 mg/kg to about 10 mg/kg of the animal's body weight.
  • the compound or compositions can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer a compound.
  • more than one compound or composition is administered to a patient.
  • administration can be by direct injection at the site (or former site) of a cancer, tumor or neoplastic or pre-neoplastic tissue. In another embodiment, administration can be by direct injection at the site (or former site) of a manifestation of an autoimmune disease.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the compound or compositions can be delivered in a controlled release system, such as but not limited to, a pump or various polymeric materials can be used.
  • a controlled-release system can be placed in proximity of the target of the compound or compositions, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Other controlled-release systems discussed in the review by Langer (1990, Science 249:1527-1533) can be used.
  • carrier refers to a diluent, adjuvant or excipient, with which a compound is administered.
  • Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
  • the compound or compositions and pharmaceutically acceptable carriers when administered to a patient, are sterile. Water is an exemplary carrier when the compounds are administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • the compounds are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to animals, particularly human beings.
  • the carriers or vehicles for intravenous administration are sterile isotonic aqueous buffer solutions.
  • the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration can optionally comprise a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions can contain one or more optionally agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • sweetening agents such as fructose, aspartame or saccharin
  • flavoring agents such as peppermint, oil of wintergreen, or cherry
  • coloring agents such as peppermint, oil of wintergreen, or cherry
  • preserving agents to provide a pharmaceutically palatable preparation.
  • the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • compositions can be intended for topical administration, in which case the carrier may be in the form of a solution, emulsion, ointment or gel base. If intended for transdermal administration, the composition can be in the form of a transdermal patch or an iontophoresis device.
  • Topical formulations can comprise a concentration of a compound of from about 0.05% to about 50% w/v (weight per unit volume of composition), in another aspect, from 0.1% to 10% w/v.
  • composition can be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the compound.
  • the composition can include various materials that modify the physical form of a solid or liquid dosage unit.
  • the composition can include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and can be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients can be encased in a gelatin capsule.
  • compositions can consist of gaseous dosage units, e.g., it can be in the form of an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery can be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients.
  • the present compositions can include a pharmacological agent used in the treatment of cancer, an autoimmune disease or an infectious disease.
  • the conjugates are useful for treating cancer, an autoimmune disease, an infectious disease or other disease in a patient.
  • the conjugates are administered alone.
  • the conjugates a co-administered with another therapeutic agent.
  • the conjugates are co-administered with standard of care chemotherapeutics.
  • the conjugates are useful for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating cancer in a patient.
  • the compounds can be used accordingly in a variety of settings for the treatment of animal cancers.
  • Some exemplary particular types of cancers that can be treated with compounds include, but are not limited to, those disclosed in Table 1.
  • Solid tumors including but not limited to: fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma Ewing's tumor leiomyosarcoma rhabdomyosarcoma colon cancer rectal cancer colorectal cancer kidney cancer pancreatic cancer bone cancer breast cancer ovarian cancer prostate cancer penile carcinoma esophogeal cancer gastric cancer gastrointestinal cancer stomach cancer peritoneal cancer hepatic carcinoma hepatocellular cancer liver cancer oral cancer nasal cancer throat cancer squamous cell carcinoma (e.g., epithelial) basal cell carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma papillary adenocarcinomas cystadenocarcinoma medullary carcinoma
  • the conjugates provide conjugation-specific tumor or cancer targeting,. thus reducing general toxicity of these compounds.
  • the linker stabilizes the conjugates in blood, yet is cleavable by enzymes within the cell (e.g., lysosomal enzymes), liberating the Drug(s).
  • Cancers including, but not limited to, a tumor, metastasis, or other disease or disorder characterized by uncontrolled cell growth, can be treated or prevented by administration of a conjugate according to the present invention.
  • methods for treating or preventing cancer including administering to a patient in need thereof an effective amount of a conjugate and a chemotherapeutic agent.
  • the chemotherapeutic agent is that with which treatment of the cancer has not been found to be refractory.
  • the chemotherapeutic agent is that with which the treatment of cancer has been found to be refractory.
  • the conjugates can be administered to a patient that has also undergone surgery as treatment for the cancer.
  • the additional method of treatment is radiation therapy.
  • the conjugate is administered concurrently with the chemotherapeutic agent or with radiation therapy.
  • the chemotherapeutic agent or radiation therapy is administered prior or subsequent to administration of a conjugate.
  • the chemotherapeutic agent or radiation therapy is administered at least an hour, five hours, 12 hours, a day, a week, a month, several months (e.g., up to three months), prior or subsequent to administration of a conjugate.
  • a chemotherapeutic agent can be administered over a series of sessions. Any one or a combination of the following chemotherapeutic agents can be administered (see infra).
  • any radiation therapy protocol can be used depending upon the type of cancer to be treated.
  • x-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers.
  • Gamma-ray emitting radioisotopes such as radioactive isotopes of radium, cobalt and other elements, can also be administered.
  • methods of treatment of cancer with a conjugate are provided as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy has proven or can prove to be too toxic, e.g., results in unacceptable or unbearable side effects, for the subject being treated.
  • the animal being treated can, optionally, be treated with another cancer treatment such as surgery, radiation therapy or chemotherapy, depending on which treatment is found to be acceptable or bearable.
  • the conjugates can also be used in an in vitro or ex vivo fashion, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas, such treatment involving autologous stem cell transplants.
  • This can involve a multi-step process in which the animal's autologous hematopoietic stem cells are harvested and purged of all cancer cells, the animal's remaining bone-marrow cell population is then eradicated via the administration of a high dose of a conjugate with or without accompanying high dose radiation therapy, and the stem cell graft is infused back into the animal. Supportive care is then provided while bone marrow function is restored and the animal recovers.
  • Methods for treating cancer including administering to a patient in need thereof an effective amount of a conjugate and another therapeutic agent that is an anti-cancer agent are disclosed.
  • chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, piposulfan and treosulfan; decarbazine; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; TLK 286 (TELCYTATM); acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue
  • anthracyclines such as annamycin, AD 32, alcarubicin, daunorubicin, dexrazoxane, DX-52-1, epirubicin, GPX-100, idarubicin, KRN5500, menogaril, dynemicin, including dynemicin A, an esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins (e.g., bleomycin A2, bleomycin B2 and peplomycin), cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-
  • the anticancer agent is methotrexate, taxol, L-asparaginase, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, topotecan, nitrogen mustards, cytoxan, etoposide, 5-fluorouracil, BCNU, irinotecan, camptothecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, or docetaxel.
  • the anti-cancer agent includes, but is not limited to, a drug listed in Table 2.
  • the conjugates are useful for killing or inhibiting the replication of a cell that produces an autoimmune disease or for treating an autoimmune disease.
  • the conjugates can be used accordingly in a variety of settings for the treatment of an autoimmune disease in a patient.
  • Th2 lymphocyte related disorders e.g., atopic dermatitis, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omenn's syndrome, systemic sclerosis, and graft versus host disease
  • Th1 lymphocyte-related disorders e.g., rheumatoid arthritis, multiple sclerosis, psoriasis, Sjorgren's syndrome, Hashimoto's thyroiditis, Grave's disease, primary biliary cirrhosis, Wegener's granulomatosis, and tuberculosis
  • activated B lymphocyte-related disorders e.g., systemic lupus erythematosus, Goodpasture's syndrome, rheumatoid arthritis, and type I diabetes
  • Methods for treating an autoimmune disease including administering to a patient in need thereof an effective amount of a conjugate and another therapeutic agent known for the treatment of an autoimmune disease.
  • the anti-autoimmune disease agent includes, but is not limited to, agents listed in Table 4.
  • the conjugates are useful for killing or inhibiting the multiplication of a cell that produces an infectious disease or for treating an infectious disease.
  • the conjugates kill or inhibit the multiplication of cells that produce a particular infectious disease.
  • Particular types of infectious diseases that can be treated with the conjugates include, but are not limited to, those disclosed in Table 5.
  • Methods for treating an infectious disease including administering to a patient in need thereof a conjugate and another therapeutic agent that is an anti-infectious disease agent.
  • the anti-infectious disease agent is, but not limited to, agents listed in Table 6.
  • Preparative HPLC purifications were performed on Varian instrument equipped with C12 Phenomenex Synergy MAX-RP 4 ⁇ reversed phase column, 250 ⁇ 21.2 mm, eluting with 0.1% TFA in a water-acetonitrile gradient. Radial chromatography was performed on a Chromatotron® instrument (Harrison Research, Palo Alto, Calif.) on normal phase silica plates (Analtech, Newark, Del.). Preparative thin layer chromatography was performed on Whatman 20 ⁇ 20 cm, 500 ⁇ , 60 ⁇ silica gel plates. All other preparative normal phase purifications were done by standard flash silica gel chromatography using Whatman Science 60 ⁇ 230-400 mesh silica gel as adsorbent.
  • MMAE Monomethyl Auristatin E
  • MMAE (1a) was prepared at Albany Molecule Research, Inc (Albany, N.Y.). The synthesis of MMAE (1a) has been described previously (Doronina et al., Nat Biotechnol 21:778-84 (2003); the disclosure of which is incorporated by reference herein).
  • MMAF Monomethyl Auristatin F
  • MMAF Carbonate (8) To a mixture of the p-nitrophenyl carbonate 7 (30 mg, 0.033 mmol) and monomethyl auristatin F (MMAF) (1b; 29 mg, 0.039 mmol) was added DMF (0.8 mL) and pyridine (0.2 mL). (The synthesis of MMAF has been described previously (Doronina et al., Bioconjug Chem. 17(1):114-124 (2006); and U.S. Patent Publication 2005-0238649; the disclosures of which are incorporated by reference herein). DIPEA (7 ⁇ L, 0.04 mmol) was added followed by HOAt (1 mg, 7 ⁇ mol). The reaction mixture was stirred for 16 h at an ambient temperature.
  • MMAF glucuronide amine To a mixture of the MMAF carbamate (22 mg, 0.015 mmol) in methanol (1 mL) at 0° C. was added a solution of LiOH monohydrate (5.5 mg, 0.132 mmol) in water (1 mL). The mixture was stirred for 15 min at 0° C. and the reaction mixture was neutralized using acetic acid (8 ⁇ L) and was concentrated under reduced pressure: LC-MS m/z (ES ⁇ ), 1364.09 (M ⁇ H) + , 9.78 min.
  • MMAF glucuronide maleimide (9b) To a mixture of the amine (12 mg, 0.011 mmol) in DMF (1 mL) was added MC-OSu (10; 5.2 mg) followed by DIPEA (6 ⁇ L). After 15 min., the reaction mixture was concentrated under reduced pressure, was dissolved in a mixture of water and DMSO (1:1; 1 mL) and was purified via preparative HPLC.
  • the oxazolidine 12 (formed from 65 mg of 4-(tert-butyidiphenylsilyloxy)butanal) was added as a dichloromethane solution (3 mL) dropwise down the cooled inside wall of the reaction flask. The reaction mixture was allowed to slowly warm to ⁇ 20° C. over several hours. The reaction mixture was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified via radial chromatography eluting with dichloromethane.
  • reaction mixture was stirred for 3 h and was poured into saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (3 ⁇ 100 mL). The combined extracts were washed with water and brine and dried over sodium sulfate, before being filtered and concentrated.
  • Drug-linkers employing a glucuronide-based linker unit with the antimitotic agents monomethyl auristatin E (MMAE; 1a) and monomethyl auristatin F (MMAF; 1b) and doxorubicin propyloxazoline (DPO; 2) were prepared and evaluated.
  • MMAE monomethyl auristatin E
  • MMAF monomethyl auristatin F
  • DPO doxorubicin propyloxazoline
  • ⁇ -Glucuronide Drug-Linker Preparation: The starting point for the synthesis of a ⁇ -glucuronide drug-linker with MMAF (1b) was ⁇ -glucuronide 5 bearing the free aniline and hydroxy groups (Scheme 3, infra). This compound was acylated with the acid chloride 6, and then converted to the p-nitrophenyl (PNP) carbonate 7. Reaction with MMAF (1b) afforded the carbamate 8. This molecule was converted to the desired glucuronide drug-linker 9b by first saponifying the acetate and methyl ester protecting groups with lithium hydroxide (Leenders et al., 1999, Bioorg. Med. Chem.
  • ADCS Antibody drug conjugates
  • linker drug conjugates 9a with MMAE
  • b with MMAF
  • 17 with doxorubicin propyloxazoline (DPO)
  • DPO doxorubicin propyloxazoline
  • the antibodies were prepared based on a method described previously (see Doronina et al., 2003, Nat. Biotechnol. 21:778-84).
  • mAbs >5 mg/ml in phosphate buffered saline (PBS) containing 50 mM sodium borate, pH 8.0, were treated with dithiothreitol (DTT) or tris(2-carboxyethyl)phospine hydrochloride (TCEP) (at 10 mM final) at 37° C. for 30 min.
  • DTT dithiothreitol
  • TCEP tris(2-carboxyethyl)phospine hydrochloride
  • Drug loading for the doxorubicin-containing conjugates cAC10-17 and c1F6-17 was determined by measuring the absorbance at 280 nm and 490 nm (doxorubicin absorbance). It was found that the cAC10 and c1F6 ADCs had 6.8 and 8.3 drugs/mAb, respectively. Due to the weak UV absorbance of the drug-linkers 9a and 9b, the drug per mAb ratios of the corresponding ADCs were determined through chromatographic resolution of the light and heavy chains at each drug loading level (0-1 drugs for light chains; 0-3 drugs for heavy chains) and calculation of the overall average from the peak areas at each loading level (Hamblett et al., supra; Sun et al., supra).
  • the levels were shown to be 3.7 and 4.5 for cAC10-9a and c1F6-9a, and 7.6 and 7.0 for the cAC10-9b and c1F6-9b conjugates, respectively.
  • the six ADCs were primarily monomeric with 2% or less aggregate being observed in the cAC10-based conjugates and 7% or less aggregate for the c1F6-based conjugates.
  • the ⁇ -glucuronide linker system described can be included a part of an antibody drug conjugate (ADC).
  • ADC antibody drug conjugate
  • ⁇ -glucuronidase e.g., a lysosomal ⁇ -glucuronidase
  • the drug-linker is hydrolyzed at the glycosidic bond and undergo a 1,6-elimination with loss of carbon dioxide to liberate drug conjugated to the linker system (see Scheme 1, supra).
  • ADCs based on this linker design employed the antimitotic drugs MMAE (1a) and MMAF (1b) and doxorubicin propyl oxazoline (DPO; 2), which is a labile precursor to highly potent 2-pyrrolinodoxorubicin (4), as shown in Scheme 2 (supra).
  • DPO doxorubicin propyl oxazoline
  • Compound 4 affects apoptosis through alkylation of double-stranded DNA (33).
  • the susceptibility of the ⁇ -glucuronide linkers to enzymatic cleavage was determined by treatment of the cysteine adduct of compound 9b with ⁇ -glucuronidase.
  • a commercially available E. coli ⁇ -glucuronidase (EC 3.2.1.31) was in place of the human enzyme for this study. This allowed confirmation that the desired drug, MMAF (1b), was released and if any stable intermediates were formed in the process.
  • AUC area under the curve
  • the ⁇ -glucuronidase assay was performed as described above. An HPLC assay was used to monitor the loss of cys-9b (MMAF) at 37° C.
  • the specific activity of the E. coli ⁇ -glucuronidase for cys-9b was 0.13 ⁇ mol/min/mg. Referring to FIG. 1 , the cleavage of ⁇ -glucuronide from cys-9b resulted in rapid 1,6-elimination of MMAF (1b) which was identified by LC-MS. No MMAF-containing phenolic intermediates could be detected by LC-MS. Thus the 1,6-elimination appears to be rapid.
  • the reactive, maleimide double bond of 9b was reduced with excess DTT to afford dihydro-9b.
  • This material was added to rat plasma and incubated at 37° C. for a period of 7 days. Aliquots were taken at various time points and the plasma proteins were precipitated, centrifuged and the supernatant recovered. Each supernatant was analyzed by LC-MS and the total positive ion current (TIC+) chromatogram was scanned for the masses of parent compound dihydro-9b and released MMAF (1b).
  • the TIC+ for dihydro-9b (including the ring-opened succinimide hydrolysis adduct) was 89% of sample taken immediately after dihydro-9b was injected into plasma. Free drug 1b could be detected but was not quantified. Assuming first order kinetics, extrapolation of these data suggest a half-life of 81 days for dihydro-9b. In a parallel experiment, the rat plasma stability of the maleimide reduced Val-Cit-PABA linked MMAF was determined, just as with dihydro-9b. This drug-linker displayed a half-life of 6.25 days.
  • the linker-drug conjugates and ADCs compounds 9a (with MMAE), 9b (MMAF) and 17 (with doxorubicin propyloxazoline (DPO) with the mAbs AC10 (IgG1 against the CD30 antigen) and 1F6 (IgG1 against the CD70 antigen) were prepared.
  • the ADCs (c1F6-9a and cAC10-9a, c1F6-9b and cAC10-9b, and c1F6-17 and cAC10-17) were evaluated for cytotoxic activity on a CD30+ cell line (Karpas 299) and two CD70+ renal cell carcinoma (RCC) lines, 786-O and Caki-1.
  • the ADCs were prepared as described above.
  • FIG. 2 In vitro evaluation of cAC10 and c1F6 conjugates of 9a demonstrated that the linker delivered active drug to the target cells with immunologic specificity ( FIG. 2 ).
  • FIG. 2A A comparison of the activity of the two conjugates on the CD30+ line Karpas 299 ( FIG. 2A ) revealed that the anti-CD30 conjugate cAC10-9a titrated to an IC 50 value of 0.06 nM (drug content), where the non-binding conjugate c1F6-9a had no cytotoxic activity up to 30 nM, the highest concentration tested.
  • the anti-CD70 conjugate c1F6-9a was quite potent on the CD70+ cell line Caki-1 (IC 50 0.45 nM) ( FIG. 2C ).
  • the ADCs of 9b effectively delivered 1 b to the targeted cells.
  • Conjugates of 9b displayed immunologic specificity and were highly effective against the CD70+ lines Caki-1 and 786-O ( FIGS. 2B and 2C , respectively) with IC 50 values of 0.08 and 0.20 nM, respectively.
  • the corresponding non-binding cAC10-9b was inactive on these cell lines representing specificity levels of >250-fold.
  • the anti-CD30 conjugate cAC10-9b was highly effective on the CD30+ line Karpas 299 with an IC 50 value of 50 ⁇ M.
  • Conjugates of doxorubicin drug-linker 17 gave the same general profile with effective cell kill on antigen positive cell lines and specificity values >16-fold.
  • cAC10-9a 4 drugs/mAb
  • MTD maximum tolerated dose
  • cAC10-9a 4 drugs/mAb
  • Conjugate c1F6-1b was well tolerated at 25 mg/kg, but was toxic at the 50 mg/kg dose.
  • the MTDs of the glucuronide ADCs therefore appear to be comparable to the corresponding peptide-linked MMAE (Doronina et al., 2003, Nat. Biotechnol. 21:778-84) and MMAF ((Doronina et al., 2006, Bioconjug. Chem. 17(1):114-124) ADCs that were previously described.
  • c1F6-9b were determined in mice with subcutaneous 786-0 renal cell carcinoma implants. Significant levels of antitumor activity were obtained at all three dose levels (0.75, 1.5 and 3.0 mg/kg), again without any signs of toxicity or adverse events ( FIG. 3B ). As with the c1F6-9a ADC, this was achieved at a small fraction of the MTD.
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Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100260786A1 (en) * 2006-02-18 2010-10-14 Seattle Genetics, Inc. Methods of treating drug-resistant cancers
WO2012092616A1 (en) 2010-12-30 2012-07-05 Takeda Pharmaceutical Company Limited Conjugated anti-cd38 antibodies
WO2014004376A2 (en) 2012-06-26 2014-01-03 Del Mar Pharmaceuticals Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof
WO2014022552A1 (en) 2012-08-02 2014-02-06 Stealth Peptides International, Inc. Methods for treatment of atherosclerosis
US20140219956A1 (en) * 2013-02-07 2014-08-07 Immunomedics, Inc. Pro-drug form (p2pdox) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer
WO2015053871A2 (en) 2013-08-26 2015-04-16 MabVax Therapeutics, Inc. NUCLEIC ACIDS ENCODING HUMAN ANTIBODIES TO SIALYL-LEWISa
WO2015187811A2 (en) 2014-06-04 2015-12-10 MabVax Therapeutics, Inc. Human monoclonal antibodies to ganglioside gd2
US9273141B2 (en) 2011-05-27 2016-03-01 Glaxo Group Limited B cell maturation antigen (BCMA) binding proteins
WO2016077260A1 (en) 2014-11-10 2016-05-19 Bristol-Myers Squibb Company Tubulysin analogs and methods of making and use
WO2016115201A1 (en) 2015-01-14 2016-07-21 Bristol-Myers Squibb Company Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using
US9683048B2 (en) 2014-01-24 2017-06-20 Novartis Ag Antibody molecules to PD-1 and uses thereof
CN107249643A (zh) * 2014-12-09 2017-10-13 艾伯维公司 具有细胞渗透性的bcl‑xl抑制剂的抗体药物缀合物
WO2018025168A1 (en) 2016-08-03 2018-02-08 Pfizer Inc. Heteroaryl sulfone-based conjugation handles, methods for their preparation, and their use in synthesizing antibody drug conjugates
WO2018035391A1 (en) 2016-08-19 2018-02-22 Bristol-Myers Squibb Company Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use
US9919057B2 (en) 2014-05-28 2018-03-20 Legochem Biosciences, Inc. Compounds comprising self-immolative group
WO2018075842A1 (en) 2016-10-20 2018-04-26 Bristol-Myers Squibb Company Condensed benzodiazepine derivatives and conjugates made therefrom
WO2018138591A1 (en) 2017-01-24 2018-08-02 Pfizer Inc. Calicheamicin derivatives and antibody drug conjugates thereof
US10118965B2 (en) 2015-09-25 2018-11-06 Legochem Biosciences, Inc. Compositions and methods related to anti-EGFR antibody drug conjugates
US10183997B2 (en) 2015-09-25 2019-01-22 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
WO2019036023A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS IMMUNOSTIMULANT TOLL (TLR7) RECEPTOR 7 AGONISTS
WO2019035971A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS TOLL 7 RECEPTOR IMMUNOSTIMULATING AGONISTS (TLR7)
WO2019035968A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS TOLL RECEPTOR 7 (TLR7) AGONISTS AS IMMUNOSTIMULANTS
WO2019035969A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company TOLL RECEPTOR 7 (TLR7) AGONISTS COMPRISING A TRICYCLIC FRAGMENT, CONJUGATES CONTAINING SAME, RELATED METHODS AND USES THEREOF
WO2019035970A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES FOR USE AS TOLL 7 RECEPTOR IMMUNOSTIMULATING AGONISTS (TLR7)
WO2019073069A1 (en) 2017-10-13 2019-04-18 Boehringer Ingelheim International Gmbh HUMAN ANTIBODIES AGAINST THOMSEN-NEW ANTIGEN (TN)
EP3501532A2 (en) 2014-05-28 2019-06-26 Stealth BioTherapeutics Corp Therapeutic compositions including frataxin, lactoferrin, and mitochondrial energy generating enzymes, and uses thereof
EP3502132A1 (en) 2014-05-28 2019-06-26 Stealth BioTherapeutics Corp Therapeutic compositions including therapeutic small molecules and uses thereof
WO2019209811A1 (en) 2018-04-24 2019-10-31 Bristol-Myers Squibb Company Macrocyclic toll-like receptor 7 (tlr7) agonists
US10472419B2 (en) 2014-01-31 2019-11-12 Novartis Ag Antibody molecules to TIM-3 and uses thereof
WO2019231879A1 (en) 2018-05-29 2019-12-05 Bristol-Myers Squibb Company Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making
WO2020028608A1 (en) 2018-08-03 2020-02-06 Bristol-Myers Squibb Company 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS AND METHODS AND USES THEREFOR
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
US10640563B2 (en) 2016-06-08 2020-05-05 Abbvie Inc. Anti-B7-H3 antibodies and antibody drug conjugates
US10973920B2 (en) 2014-06-30 2021-04-13 Glykos Finland Oy Saccharide derivative of a toxic payload and antibody conjugates thereof
US11103593B2 (en) 2013-10-15 2021-08-31 Seagen Inc. Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics
US11116847B2 (en) 2013-12-19 2021-09-14 Seagen Inc. Methylene carbamate linkers for use with targeted-drug conjugates
US11167040B2 (en) 2015-11-25 2021-11-09 Legochem Biosciences, Inc. Conjugates comprising peptide groups and methods related thereto
US11173214B2 (en) 2015-11-25 2021-11-16 Legochem Biosciences, Inc. Antibody-drug conjugates comprising branched linkers and methods related thereto
US11229708B2 (en) 2015-12-04 2022-01-25 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11344620B2 (en) 2014-09-13 2022-05-31 Novartis Ag Combination therapies
US11413353B2 (en) 2015-11-25 2022-08-16 Legochem Biosciences, Inc. Conjugates comprising self-immolative groups and methods related thereto
US11491154B2 (en) 2013-04-08 2022-11-08 Dennis M. Brown Therapeutic benefit of suboptimally administered chemical compounds
US11654197B2 (en) 2017-03-29 2023-05-23 Legochem Biosciences, Inc. Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
US11707533B2 (en) 2019-09-04 2023-07-25 Legochem Biosciences, Inc. Antibody-drug conjugate comprising antibody against human ROR1 and use for the same
US11730822B2 (en) 2017-03-24 2023-08-22 Seagen Inc. Process for the preparation of glucuronide drug-linkers and intermediates thereof
US11759527B2 (en) 2021-01-20 2023-09-19 Abbvie Inc. Anti-EGFR antibody-drug conjugates
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11827703B2 (en) 2018-05-09 2023-11-28 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
US11844839B2 (en) 2016-03-25 2023-12-19 Seagen Inc. Process for the preparation of pegylated drug-linkers and intermediates thereof

Families Citing this family (143)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100056762A1 (en) 2001-05-11 2010-03-04 Old Lloyd J Specific binding proteins and uses thereof
US20110313230A1 (en) 2001-05-11 2011-12-22 Terrance Grant Johns Specific binding proteins and uses thereof
WO2002092771A2 (en) 2001-05-11 2002-11-21 Ludwig Institute For Cancer Research Specific binding proteins and uses thereof
PL3248613T3 (pl) * 2005-07-18 2022-04-19 Seagen Inc. Koniugaty β-glukuronid-linker-lek
WO2007140371A2 (en) 2006-05-30 2007-12-06 Genentech, Inc. Antibodies and immunoconjugates and uses therefor
PT2845866T (pt) 2006-10-27 2017-08-09 Genentech Inc Anticorpos e imunoconjugados e utilizações dos mesmos
EP2126127B1 (en) 2007-01-25 2016-09-28 Dana-Farber Cancer Institute, Inc. Use of anti-egfr antibodies in treatment of egfr mutant mediated disease
AU2008227123B2 (en) 2007-03-15 2014-03-27 Ludwig Institute For Cancer Research Ltd. Treatment method using EGFR antibodies and src inhibitors and related formulations
FR2914306B1 (fr) * 2007-04-02 2009-07-03 Biocydex Soc Par Actions Simpl Oligomeres de cyclodextrines, vecteurs de molecules actives
SG183023A1 (en) 2007-07-16 2012-08-30 Genentech Inc Anti-cd79b antibodies and immunoconjugates and methods of use
EP2641618A3 (en) 2007-07-16 2013-10-23 Genentech, Inc. Humanized anti-CD79B antibodies and immunoconjugates and methods of use
EP2188311B1 (en) 2007-08-14 2016-10-05 Ludwig Institute for Cancer Research Ltd. Monoclonal antibody 175 targeting the egf receptor and derivatives and uses thereof
FR2920877B1 (fr) * 2007-09-10 2010-01-22 Commissariat Energie Atomique Substrats fluorescents saccharidiques, leur procede de procede de preparation et leurs utisations.
AU2008310908B2 (en) 2007-10-12 2014-01-09 Seagen Inc. Combination therapy with antibody-drug conjugates
CA2702555A1 (en) * 2007-10-19 2009-04-23 Seattle Genetics, Inc. Cd19 binding agents and uses thereof
IL295449A (en) 2008-01-31 2022-10-01 Genentech Inc and fusion antibody-drug-cd79b engineered antibodies cysteine-
ES2547552T3 (es) * 2008-02-01 2015-10-07 Genentech, Inc. Metabolito de nemorrubicina y reactivos análogos, conjugados anticuerpo-fármaco y métodos
CA2727915C (en) 2008-07-15 2016-04-26 Genentech, Inc. Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds
ES2438495T3 (es) 2008-09-08 2014-01-17 Psma Development Company, L.L.C. Compuestos para exterminar células cancerosas que expresan PSMA, resistentes a taxano
PE20120878A1 (es) 2009-04-01 2012-08-06 Genentech Inc ANTICUERPOS ANTI-FcRH5 E INMUNOCONJUGADOS
US20110076232A1 (en) 2009-09-29 2011-03-31 Ludwig Institute For Cancer Research Specific binding proteins and uses thereof
CN103068405A (zh) * 2010-04-15 2013-04-24 西雅图基因公司 靶向吡咯并苯并二氮杂卓结合物
KR20130098165A (ko) 2010-06-03 2013-09-04 제넨테크, 인크. 항체 및 면역접합체의 이뮤노-ｐｅｔ 영상화 및 그의 용도
RU2563638C2 (ru) 2010-12-02 2015-09-20 НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. Способ получения производных морфолинилантрациклина
WO2012094653A2 (en) * 2011-01-07 2012-07-12 Massachusetts Institute Of Technology Compositions and methods for macromolecular drug delivery
ES2531471T3 (es) * 2011-02-25 2015-03-16 Lonza Ltd Enlazador ramificado para conjugados de proteínas-fármacos
CN104906592B (zh) * 2011-02-25 2017-11-03 广州南沙龙沙有限公司 用于蛋白质药物偶联物的支链联接体
WO2012151039A2 (en) * 2011-05-02 2012-11-08 The Regents Of The University Of California Compositions and methods for detecting mycobacterium
RS59253B1 (sr) 2011-05-08 2019-10-31 Legochem Biosciences Inc Konjugati aktivnog agensa proteina i postupak za njihovo dobijanje
WO2012158964A2 (en) * 2011-05-18 2012-11-22 Eumederis Pharmaceuticals, Inc. Improved peptide pharmaceuticals for osteoporosis
CN107043339B (zh) * 2011-07-19 2019-09-06 希默赛生物技术有限责任公司 新交联试剂、大分子、治疗用偶联物及其合成方法
WO2013067055A1 (en) 2011-11-01 2013-05-10 Bionomics, Inc. Methods of blocking cancer stem cell growth
EP2592103A1 (en) 2011-11-08 2013-05-15 Adriacell S.p.A. Polymer aldehyde derivatives
ES2725569T3 (es) 2012-02-10 2019-09-24 Seattle Genetics Inc Diagnóstico y tratamiento de cánceres que expresan CD30
US9353150B2 (en) 2012-12-04 2016-05-31 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment
CA2906784C (en) 2013-03-15 2023-02-28 The Centre For Drug Research And Development Cytotoxic and anti-mitotic compounds, and methods of using the same
PT2968588T (pt) 2013-03-15 2019-05-08 Abbvie Inc Formulações de conjugado de fármaco-anticorpo anti-egfr
US9498540B2 (en) 2013-03-15 2016-11-22 Novartis Ag Cell proliferation inhibitors and conjugates thereof
SG11201507432XA (en) 2013-03-15 2015-10-29 Abbvie Inc Antibody drug conjugate (adc) purification
DK2991683T3 (da) * 2013-05-02 2019-11-04 Glykos Finland Oy Konjugater af et glykoprotein eller en glykan med en toksisk ladning
US10208125B2 (en) 2013-07-15 2019-02-19 University of Pittsburgh—of the Commonwealth System of Higher Education Anti-mucin 1 binding agents and uses thereof
KR102384740B1 (ko) 2013-12-27 2022-04-07 자임워크스 인코포레이티드 약물 접합체를 위한 설폰아마이드-함유 연결 시스템
FR3017298B1 (fr) * 2014-02-07 2016-03-04 Centre Nat Rech Scient Conjugues et pro-drogues pour le traitement du cancer et de maladies inflammatoires
KR20220025946A (ko) 2014-03-21 2022-03-03 애브비 인코포레이티드 항-ｅｇｆｒ 항체 및 항체 약물 접합체
EP3154587B1 (en) 2014-06-13 2020-01-15 Tenboron OY Conjugates comprising an anti-egfr1 antibody
US9879086B2 (en) 2014-09-17 2018-01-30 Zymeworks Inc. Cytotoxic and anti-mitotic compounds, and methods of using the same
EP3212668B1 (en) 2014-10-31 2020-10-14 AbbVie Biotherapeutics Inc. Anti-cs1 antibodies and antibody drug conjugates
CA2970155A1 (en) 2014-12-09 2016-06-16 Abbvie Inc. Bcl-xl inhibitory compounds having low cell permeability and antibody drug conjugates including the same
JP6864953B2 (ja) 2014-12-09 2021-04-28 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル Ａｘｌに対するヒトモノクローナル抗体
EP3270965B1 (en) 2015-03-18 2020-05-06 Seattle Genetics, Inc. Cd48 antibodies and conjugates thereof
US11014953B2 (en) 2015-10-07 2021-05-25 The Board Of Trustees Of The University Of Illinois Trigger-activatable metabolic sugar precursors for cancer-selective labeling and targeting
WO2017060397A1 (en) 2015-10-09 2017-04-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of subjects suffering from melanoma metastases
WO2017067944A1 (en) 2015-10-19 2017-04-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for predicting the survival time of subjects suffering from triple negative breast cancer
JP6412906B2 (ja) * 2015-11-03 2018-10-24 財團法人工業技術研究院Ｉｎｄｕｓｔｒｉａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ 化合物、リンカー−薬物およびリガンド−薬物複合体
JP2019500327A (ja) 2015-11-30 2019-01-10 アッヴィ・インコーポレイテッド 抗ｈｕＬＲＲＣ１５抗体薬物コンジュゲート及びその使用方法
EP3383910A1 (en) 2015-11-30 2018-10-10 AbbVie Inc. ANTI-huLRRC15 ANTIBODY DRUG CONJUGATES AND METHODS FOR THEIR USE
US11013690B2 (en) * 2016-01-04 2021-05-25 Academia Sinica Esterification/saponification-based method for liposomal encapsulation of hydrophilic glucuronides
WO2017162678A1 (en) 2016-03-22 2017-09-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Humanized anti-claudin-1 antibodies and uses thereof
CN108697799A (zh) 2016-03-22 2018-10-23 生态学有限公司 抗lgr5单克隆抗体的施用
WO2017197045A1 (en) 2016-05-11 2017-11-16 Movassaghi Mohammad Convergent and enantioselective total synthesis of communesin analogs
DK3458102T3 (da) 2016-05-17 2020-07-27 Abbvie Biotherapeutics Inc Anti-cmet-antistoflægemiddelkonjugater og fremgangsmåder til anvendelse deraf
WO2017214301A1 (en) 2016-06-08 2017-12-14 Abbvie Inc. Anti-egfr antibody drug conjugates
JP2019526529A (ja) 2016-06-08 2019-09-19 アッヴィ・インコーポレイテッド 抗ｂ７−ｈ３抗体及び抗体薬物コンジュゲート
CN109562169A (zh) 2016-06-08 2019-04-02 艾伯维公司 抗cd98抗体及抗体药物偶联物
CR20180614A (es) 2016-06-08 2019-07-29 Abbvie Inc Conjugados de anticuerpo y fármaco anti-egfr
CN109600993A (zh) 2016-06-08 2019-04-09 艾伯维公司 抗egfr抗体药物偶联物
CN109641962A (zh) 2016-06-08 2019-04-16 艾伯维公司 抗b7-h3抗体和抗体药物偶联物
US20200121803A1 (en) 2016-06-08 2020-04-23 Abbvie Inc. Anti-cd98 antibodies and antibody drug conjugates
US20200147235A1 (en) 2016-06-08 2020-05-14 Abbvie Inc. Anti-cd98 antibodies and antibody drug conjugates
EA201990470A1 (ru) 2016-08-09 2019-09-30 Сиэтл Дженетикс, Инк. Конъюгаты лекарственного средства с самостабилизирующимися линкерами, имеющие улучшенные физико-химические свойства
CN110121508A (zh) 2016-10-25 2019-08-13 法国国家健康和医学研究院 与cd160跨膜同种型结合的单克隆抗体
CN109996543A (zh) * 2016-11-14 2019-07-09 醣基生医股份有限公司 抗体药物复合体
JP2019533711A (ja) * 2016-11-14 2019-11-21 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 非成人のヒトに対する抗ｃｄ３０抗体−薬物コンジュゲートの投与
PL3544634T3 (pl) * 2016-11-23 2021-09-27 Eli Lilly And Company Koniugaty przeciwciało MET-lek
US11135307B2 (en) 2016-11-23 2021-10-05 Mersana Therapeutics, Inc. Peptide-containing linkers for antibody-drug conjugates
JP7244987B2 (ja) 2016-12-14 2023-03-23 シージェン インコーポレイテッド 多剤抗体薬物コンジュゲート
KR102085798B1 (ko) 2016-12-28 2020-03-06 주식회사 인투셀 베타-갈락토사이드가 도입된 자가-희생 기를 포함하는 화합물
WO2018146253A1 (en) 2017-02-10 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the mapk pathway
EP3595729A4 (en) * 2017-02-10 2022-01-12 The Board of Trustees of the University of Illinois TRIGGER-ACTIVATED SUGAR CONJUGATES FOR CANCER SELECTIVE LABELING AND TARGETING
WO2018209239A1 (en) 2017-05-11 2018-11-15 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US11666657B2 (en) 2017-05-16 2023-06-06 Universite De Strasbourg Protein-drug conjugates and their use in the treatment of cancers
EP3641802A1 (en) 2017-06-22 2020-04-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of fibrosis with agents capable of inhibiting the activation of mucosal-associated invariant t (mait) cells
WO2019051488A1 (en) 2017-09-11 2019-03-14 Sperovie Biosciences, Inc. COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISEASE
US11707531B2 (en) 2017-09-11 2023-07-25 F-star Therapeutics, Inc. Compounds, compositions, and methods for the treatment of disease
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
EP3498293A1 (en) 2017-12-15 2019-06-19 Institut National De La Sante Et De La Recherche Medicale (Inserm) Treatment of monogenic diseases with an anti-cd45rc antibody
JP7460608B2 (ja) 2018-05-07 2024-04-02 ジェンマブ エー／エス 抗ｐｄ－１抗体と抗組織因子抗体－薬物コンジュゲートとの組み合わせを用いるがんの治療方法
AU2019266205A1 (en) 2018-05-07 2020-10-22 Genmab A/S Methods of treating cancer with a combination of an anti-PD-1 antibody and an anti-tissue factor antibody-drug conjugate
PE20210320A1 (es) 2018-06-01 2021-02-16 Novartis Ag Moleculas de union contra bcma y usos de las mismas
CN113382754A (zh) * 2018-07-13 2021-09-10 Il-2Rx公司 治疗癌症和免疫病症的化合物、组合物、方法和用途
JP2020019723A (ja) * 2018-07-30 2020-02-06 国立大学法人 鹿児島大学 抗ＣＤ７０抗体とＩｇＧ結合ペプチドの複合体
WO2020058372A1 (en) 2018-09-19 2020-03-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of cancers resistant to immune checkpoint therapy
EP3626265A1 (en) 2018-09-21 2020-03-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Anti-human cd45rc antibodies and uses thereof
GB201817321D0 (en) 2018-10-24 2018-12-05 Nanna Therapeutics Ltd Microbeads for tagless encoded chemical library screening
TW202034958A (zh) 2018-10-30 2020-10-01 丹麥商珍美寶股份有限公司 使用抗血管內皮生長因子（ｖｅｇｆ）抗體與抗組織因子（ｔｆ）抗體－藥物共軛體之組合以治療癌症之方法
JP2022512860A (ja) 2018-11-06 2022-02-07 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル 白血病幹細胞を根絶することによる急性骨髄性白血病の治療のための方法および医薬組成物
WO2020120786A1 (en) 2018-12-14 2020-06-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Isolated mhc-derived human peptides and uses thereof for stimulating and activating the suppressive function of cd8+cd45rclow tregs
JP2022519273A (ja) 2019-02-05 2022-03-22 シージェン インコーポレイテッド 抗ｃｄ２２８抗体及び抗体薬物コンジュゲート
WO2020187998A1 (en) 2019-03-19 2020-09-24 Fundació Privada Institut D'investigació Oncològica De Vall Hebron Combination therapy with omomyc and an antibody binding pd-1 or ctla-4 for the treatment of cancer
WO2020236792A1 (en) 2019-05-21 2020-11-26 Novartis Ag Cd19 binding molecules and uses thereof
US20230071196A1 (en) 2019-05-21 2023-03-09 Novartis Ag Variant cd58 domains and uses thereof
US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof
JP2022543669A (ja) 2019-08-08 2022-10-13 リジェネロン・ファーマシューティカルズ・インコーポレイテッド 新規抗原結合分子フォーマット
CA3149494A1 (en) 2019-08-12 2021-02-18 Purinomia Biotech, Inc. Methods and compositions for promoting and potentiating t-cell mediated immune responses through adcc targeting of cd39 expressing cells
EP4025233A4 (en) * 2019-09-04 2023-07-12 Seagen Inc. DOUBLE DIGESTIVE ASSAY FOR THE ANALYSIS OF LIGAND-DRUG CONJUGATES
MX2022003268A (es) 2019-09-19 2022-06-02 Seagen Inc Liberacion selectiva de farmaco a partir de conjugados internalizados de compuestos biologicamente activos.
US20220363776A1 (en) 2019-10-04 2022-11-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer
TW202134277A (zh) 2019-11-05 2021-09-16 美商再生元醫藥公司 Ｎ—端ｓｃＦｖ多特異性結合分子
TW202131954A (zh) 2019-11-07 2021-09-01 丹麥商珍美寶股份有限公司 利用鉑類劑與抗組織因子抗體－藥物共軛體之組合來治療癌症之方法
JP2023500888A (ja) 2019-11-07 2023-01-11 ジェンマブ エー／エス 抗ｐｄ－１抗体と抗組織因子抗体－薬物コンジュゲートとの組み合わせを用いるがんの治療方法
TW202138388A (zh) 2019-12-30 2021-10-16 美商西根公司 以非海藻糖苷化抗－ｃｄ７０抗體治療癌症之方法
CA3174103A1 (en) 2020-03-06 2021-09-10 Go Therapeutics, Inc. Anti-glyco-cd44 antibodies and their uses
WO2021195513A1 (en) 2020-03-27 2021-09-30 Novartis Ag Bispecific combination therapy for treating proliferative diseases and autoimmune disorders
BR112022020332A2 (pt) 2020-04-10 2022-12-13 Seagen Inc Composto conjugado anticorpo-droga, composição, método de tratamento de câncer e de um distúrbio autoimune
CA3182333A1 (en) 2020-05-20 2021-11-25 Institut Curie Single domain antibodies and their use in cancer therapies
BR112022025105A2 (pt) 2020-06-29 2023-01-17 Genmab As Método para o tratamento de câncer cervical em um indivíduo, conjugado anticorpo-fármaco, e, uso de um conjugado anticorpo-fármaco
US20230323299A1 (en) 2020-08-03 2023-10-12 Inserm (Institut National De La Santé Et De La Recherch Médicale) Population of treg cells functionally committed to exert a regulatory activity and their use for adoptive therapy
CN112062855A (zh) 2020-08-26 2020-12-11 康诺亚生物医药科技（成都）有限公司 一种含有衔接器的药物治疗剂的开发和应用
EP4229090A1 (en) 2020-10-16 2023-08-23 Université d'Aix-Marseille Anti-gpc4 single domain antibodies
CN114685657A (zh) 2020-12-31 2022-07-01 康诺亚生物医药科技（成都）有限公司 一种功能增强型抗体阻断剂的开发及其应用
JP2024505428A (ja) 2021-01-14 2024-02-06 アンスティテュ キュリー Ｈｅｒ２単一ドメイン抗体バリアントおよびそのｃａｒ
BR112023014128A2 (pt) 2021-01-15 2023-10-31 Seagen Inc Conjugados de anticorpo-fármaco imunomodulatórios
JP2023553520A (ja) 2021-01-19 2023-12-21 エリモス・ファーマシューティカルズ・リミテッド・ライアビリティ・カンパニー コロナウイルス抗ウイルス剤としてのテラメプロコールおよびノルジヒドログアイアレチン酸（ｎｄｇａ）誘導体
CA3206244A1 (en) 2021-02-03 2022-08-11 Kung-Pern WANG Immunostimulatory compounds and conjugates
EP4301782A1 (en) 2021-03-05 2024-01-10 Go Therapeutics, Inc. Anti-glyco-cd44 antibodies and their uses
CA3213625A1 (en) 2021-03-18 2022-09-22 Seagen Inc. Selective drug release from internalized conjugates of biologically active compounds
AU2022238571A1 (en) 2021-03-18 2023-09-14 Seagen Inc. Selective drug release from internalized conjugates of biologically active compounds
JP2024512567A (ja) 2021-03-23 2024-03-19 インサーム（インスティテュ ナシオナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシェ メディカル） Ｔ細胞リンパ腫の診断および治療方法
WO2022214681A1 (en) 2021-04-09 2022-10-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of anaplastic large cell lymphoma
KR20240015670A (ko) 2021-05-28 2024-02-05 씨젠 인크. 안트라사이클린 항체 접합체
AU2022324456A1 (en) 2021-08-05 2024-02-15 Go Therapeutics, Inc. Anti-glyco-muc4 antibodies and their uses
WO2023034571A1 (en) 2021-09-03 2023-03-09 Go Therapeutics, Inc. Anti-glyco-lamp1 antibodies and their uses
AU2022339667A1 (en) 2021-09-03 2024-04-11 Go Therapeutics, Inc. Anti-glyco-cmet antibodies and their uses
WO2023041717A1 (en) 2021-09-16 2023-03-23 Aboleris Pharma Anti-human cd45rc binding domains and uses thereof
WO2023110937A1 (en) 2021-12-14 2023-06-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Depletion of nk cells for the treatment of adverse post-ischemic cardiac remodeling
WO2023144303A1 (en) 2022-01-31 2023-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Cd38 as a biomarker and biotarget in t-cell lymphomas
WO2023198648A1 (en) 2022-04-11 2023-10-19 Institut National de la Santé et de la Recherche Médicale Methods for the diagnosis and treatment of t-cell malignancies
WO2023198874A1 (en) 2022-04-15 2023-10-19 Institut National de la Santé et de la Recherche Médicale Methods for the diagnosis and treatment of t cell-lymphomas
WO2023213960A1 (en) 2022-05-06 2023-11-09 Genmab A/S Methods of treating cancer with anti-tissue factor antibody-drug conjugates
WO2023215740A1 (en) 2022-05-06 2023-11-09 Seagen Inc. Immunomodulatory antibody-drug conjugates
WO2024005460A1 (ko) * 2022-06-27 2024-01-04 주식회사 트리오어 자가-희생기를 포함하는 화합물 및 이를 포함하는 리간드-약물 접합체
WO2024030577A1 (en) 2022-08-03 2024-02-08 Seagen Inc. Immunostimulatory anti-pd-l1-drug conjugates
WO2024052685A1 (en) 2022-09-09 2024-03-14 MyricX Pharma Limited Cytotoxic imidazo[1,2-a]pyridine compounds and their use in therapy

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5561119A (en) 1991-04-30 1996-10-01 Laboratoires Hoechst Glycosylated prodrugs, their method of preparation and their uses
US5851527A (en) * 1988-04-18 1998-12-22 Immunomedics, Inc. Method for antibody targeting of therapeutic agents
US6361774B1 (en) 1999-09-17 2002-03-26 Immunomedics, Inc. Methods and compositions for increasing the target-specific toxicity of a chemotherapy drug
WO2003086312A2 (en) 2002-04-12 2003-10-23 A & D Bioscience, Inc. Conjugates comprising cancer cell specific ligands, a sugar and cancer chemotherapeutic agents/boron neutron capture therapy agents, and uses thereof
WO2004010957A2 (en) 2002-07-31 2004-02-05 Seattle Genetics, Inc. Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
US6884869B2 (en) 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
US6906182B2 (en) 2000-12-01 2005-06-14 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and method of use

Family Cites Families (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2036891B (en) 1978-12-05 1983-05-05 Windsor Smith C Change speed gear
CA1213229A (en) 1982-04-12 1986-10-28 Gary S. David Antibodies having dual specificities, their preparation and uses therefor
US4486414A (en) 1983-03-21 1984-12-04 Arizona Board Of Reagents Dolastatins A and B cell growth inhibitory substances
GB8308235D0 (en) 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
JPS6147500A (ja) 1984-08-15 1986-03-07 Res Dev Corp Of Japan キメラモノクロ−ナル抗体及びその製造法
EP0173494A3 (en) 1984-08-27 1987-11-25 The Board Of Trustees Of The Leland Stanford Junior University Chimeric receptors by dna splicing and expression
GB8422238D0 (en) 1984-09-03 1984-10-10 Neuberger M S Chimeric proteins
JPS61134325A (ja) 1984-12-04 1986-06-21 Teijin Ltd ハイブリツド抗体遺伝子の発現方法
CA1282069C (en) 1985-09-12 1991-03-26 Damon L. Meyer Antibody complexes of hapten-modified diagnostic or therapeutic agents
DE3689123T2 (de) 1985-11-01 1994-03-03 Xoma Corp Modulare einheit von antikörpergenen, daraus hergestellte antikörper und verwendung.
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US4816444A (en) 1987-07-10 1989-03-28 Arizona Board Of Regents, Arizona State University Cell growth inhibitory substance
US5076973A (en) 1988-10-24 1991-12-31 Arizona Board Of Regents Synthesis of dolastatin 3
US5047335A (en) 1988-12-21 1991-09-10 The Regents Of The University Of Calif. Process for controlling intracellular glycosylation of proteins
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US4978744A (en) 1989-01-27 1990-12-18 Arizona Board Of Regents Synthesis of dolastatin 10
US4879278A (en) 1989-05-16 1989-11-07 Arizona Board Of Regents Isolation and structural elucidation of the cytostatic linear depsipeptide dolastatin 15
US4986988A (en) 1989-05-18 1991-01-22 Arizona Board Of Regents Isolation and structural elucidation of the cytostatic linear depsipeptides dolastatin 13 and dehydrodolastatin 13
DE3920358A1 (de) 1989-06-22 1991-01-17 Behringwerke Ag Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung
US5138036A (en) 1989-11-13 1992-08-11 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation and structural elucidation of the cytostatic cyclodepsipeptide dolastatin 14
DE69133566T2 (de) 1990-01-12 2007-12-06 Amgen Fremont Inc. Bildung von xenogenen Antikörpern
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
DK0814159T3 (da) 1990-08-29 2005-10-24 Genpharm Int Transgene, ikke-humane dyr, der er i stand til at danne heterologe antistoffer
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5278299A (en) 1991-03-18 1994-01-11 Scripps Clinic And Research Foundation Method and composition for synthesizing sialylated glycosyl compounds
WO1993008829A1 (en) 1991-11-04 1993-05-13 The Regents Of The University Of California Compositions that mediate killing of hiv-infected cells
AU3144193A (en) 1991-11-21 1993-06-15 Board Of Trustees Of The Leland Stanford Junior University Controlling degradation of glycoprotein oligosaccharides by extracellular glycosisases
EP0617706B1 (en) 1991-11-25 2001-10-17 Enzon, Inc. Multivalent antigen-binding proteins
CA2140280A1 (en) 1992-08-17 1994-03-03 Avi J. Ashkenazi Bispecific immunoadhesins
US5635483A (en) 1992-12-03 1997-06-03 Arizona Board Of Regents Acting On Behalf Of Arizona State University Tumor inhibiting tetrapeptide bearing modified phenethyl amides
US6034065A (en) 1992-12-03 2000-03-07 Arizona Board Of Regents Elucidation and synthesis of antineoplastic tetrapeptide phenethylamides of dolastatin 10
US5410024A (en) 1993-01-21 1995-04-25 Arizona Board Of Regents Acting On Behalf Of Arizona State University Human cancer inhibitory pentapeptide amides
US5780588A (en) 1993-01-26 1998-07-14 Arizona Board Of Regents Elucidation and synthesis of selected pentapeptides
US5434105A (en) * 1994-03-04 1995-07-18 National Semiconductor Corporation Process for attaching a lead frame to a heat sink using a glob-top encapsulation
US5504191A (en) 1994-08-01 1996-04-02 Arizona Board Of Regents Acting On Behalf Of Arizona State University Human cancer inhibitory pentapeptide methyl esters
US5521284A (en) 1994-08-01 1996-05-28 Arizona Board Of Regents Acting On Behalf Of Arizona State University Human cancer inhibitory pentapeptide amides and esters
US5530097A (en) 1994-08-01 1996-06-25 Arizona Board Of Regents Acting On Behalf Of Arizona State University Human cancer inhibitory peptide amides
US5554725A (en) 1994-09-14 1996-09-10 Arizona Board Of Regents Acting On Behalf Of Arizona State University Synthesis of dolastatin 15
US5599902A (en) 1994-11-10 1997-02-04 Arizona Board Of Regents Acting On Behalf Of Arizona State University Cancer inhibitory peptides
US5663149A (en) 1994-12-13 1997-09-02 Arizona Board Of Regents Acting On Behalf Of Arizona State University Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides
US5739277A (en) 1995-04-14 1998-04-14 Genentech Inc. Altered polypeptides with increased half-life
CA2249195A1 (en) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
US6130237A (en) 1996-09-12 2000-10-10 Cancer Research Campaign Technology Limited Condensed N-aclyindoles as antitumor agents
DE69832158T2 (de) 1997-02-25 2006-08-10 Arizona Board Of Regents, Tempe Isolierung und strukturelle aufklärung der kryostatischen linearen und cyclo-depsipeptide dolastatin 16, dolastatin 17, und dolastatin 18
ATE472599T1 (de) 1997-11-21 2010-07-15 Human Genome Sciences Inc Chemokin alpha-5
US6323315B1 (en) 1999-09-10 2001-11-27 Basf Aktiengesellschaft Dolastatin peptides
US7063845B2 (en) 2000-04-28 2006-06-20 Gemini Science, Inc. Human anti-CD40 antibodies
US20030083263A1 (en) 2001-04-30 2003-05-01 Svetlana Doronina Pentapeptide compounds and uses related thereto
AR039067A1 (es) 2001-11-09 2005-02-09 Pfizer Prod Inc Anticuerpos para cd40
KR100668538B1 (ko) 2002-01-09 2007-01-16 메다렉스, 인코포레이티드 Ｃｄ３０에 대한 인간 모노클로날 항체
US7641609B2 (en) 2002-07-31 2010-01-05 Olympus Corporation Endoscope device and navigation method for endoscope device
ES2347959T3 (es) 2003-02-20 2010-11-26 Seattle Genetics, Inc. Conjugados de anticuerpos anti-cd70-farmaco y su uso para el tratamiento del cancer.
SG149815A1 (en) 2003-11-06 2009-02-27 Seattle Genetics Inc Monomethylvaline compounds capable of conjugation to ligands
US20060003412A1 (en) 2003-12-08 2006-01-05 Xencor, Inc. Protein engineering with analogous contact environments
PL3248613T3 (pl) * 2005-07-18 2022-04-19 Seagen Inc. Koniugaty β-glukuronid-linker-lek

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5851527A (en) * 1988-04-18 1998-12-22 Immunomedics, Inc. Method for antibody targeting of therapeutic agents
US5561119A (en) 1991-04-30 1996-10-01 Laboratoires Hoechst Glycosylated prodrugs, their method of preparation and their uses
US6361774B1 (en) 1999-09-17 2002-03-26 Immunomedics, Inc. Methods and compositions for increasing the target-specific toxicity of a chemotherapy drug
US6906182B2 (en) 2000-12-01 2005-06-14 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and method of use
US6884869B2 (en) 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
WO2003086312A2 (en) 2002-04-12 2003-10-23 A & D Bioscience, Inc. Conjugates comprising cancer cell specific ligands, a sugar and cancer chemotherapeutic agents/boron neutron capture therapy agents, and uses thereof
WO2004010957A2 (en) 2002-07-31 2004-02-05 Seattle Genetics, Inc. Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease

Non-Patent Citations (53)

* Cited by examiner, † Cited by third party
Title
Albin, N. et al., "Main Drug-metabolizing Enzyme Systems in Human Breast Tumors and Peritumoral Tissues," Cancer Research, Aug. 1, 1993, vol. 53, pp. 3541-3546.
Allen, T.M., "Ligand-Targeted Therapeutics in Anticancer Therapy," Nature, Oct. 2002, vol. 2, pp. 750-763.
Andrianomenjanahary, S. et al., "Synthesis of Novel Targeted Pro-Prodrugs of Anthracyclines Potentially Activated by a Monoclonal Antibody Galactosidase Conjugate (Part 1)," Bioorganic & Medicinal Chemistry Letters, 1992, vol. 2, No. 9, pp. 1093-1096.
Angenault, S. et al., "Cancer Chemotherapy: A SN-38 (7-Ethyl-10-hydroxycamptothecin) Glucuronide Prodrug for Treatment by a PMT (Prodrug MonoTherapy) Strategy," Bioorganic & Medicinal Chemistry Letters, 2003, vol. 13, pp. 947-950.
Asai, A. et al., "synthesis and Antitumor Activity of Water-soluble Duocarmycin B1 Prodrugs," Bioorganic & Medicinal Chemistry Letters, 1999, vol. 9, pp. 2995-2998.
Azoulay, M. et al., "Prodrugs of anthracycline antibiotics suited for tumor-specific activation," Anti-Cancer Drug Design, 1995, vol. 10, pp. 441-460.
Bakina, E. et al., "Intensely Cytotoxic Anthracycline Prodrugs: Glucuronides," J. Med. Chem., 1997, vol. 40, No. 25, pp. 4013-4018.
Boons, G-J., ed., Carbohydrate Chemistry, Blackie Academic & Professional: London, United Kingdom, 1998, pp. 98-174.
Bosslet, K. et al., "Elucidation of the Mechanism Enabling Tumor Selective Prodrug Monotherapy," Cancer Research, Mar. 15, 1998, vol. 58, pp. 1195-1201.
Bross, P.F. et al., "Approval Summary: Gemtuzumab Ozogamicin in Relapsed Acute Myeloid Leukemia," Clinical Cancer Research, Jun. 2001, vol. 7, pp. 1490-1496.
Chen, X. et al., "Glucuronides in Anti-Cancer Therapy," Curr. Med. Chem.-Anti-Cancer Agents, 2003, vol. 3, No. 2, pp. 139-150.
De Graaf, M. et al. "Cytosolic beta-glycosidases for activation of glycoside prodrugs of daunorubicin," Biochemical Pharmacology, 2003, vol. 65, pp. 1875-1881.
De Graaf, M. et al. "Cytosolic β-glycosidases for activation of glycoside prodrugs of daunorubicin," Biochemical Pharmacology, 2003, vol. 65, pp. 1875-1881.
De Graaf, M. et al., "Beta-Glucuronidase-Mediated Drug Release,"Current Pharmaceutical Design, 2002, vol. 8, No. 15, pp. 1391-1403.
De Groot, F.M.H., et al., "Anticancer Prodrugs for Application in Monotherapy: Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors," Current Medicinal Chemistry, 2001, vol. 8, No. 9, pp. 1093-1122.
Desai, A.A. et al., "UGT pharmcogenomics: implications for cancer risk and cancer therapeutics," Pharmacogenetics, 2003, vol. 13, No. 8, pp. 517-523.
Desbéne, S. et al., "Doxorubicin prodrugs with reduced cytotoxicity suited for tumour-specific activation," Anti-Cancer Dru Design, 1998, vol. 13, pp. 955-968.
Drueckhammer, D.G. et al., "Enzyme Catalysis in Synthetic Carbohydrate Chemistry," Synthesis, Jul. 1991, pp. 499-525.
Dubowchik, G.M. et al., "Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs," Pharmacology & Therapeutics, 1999, vol. 83, pp. 67-123.
Eneyskaya, E.V. et al., "Chemo-enzymatic synthesis of 4-methylumbelliferyl beta-(1->4)-D-xylooligosides: new substrates for beta-D-xylanease assaus," Org. Biomol. Chem., 2005, vol. 3, pp. 146-151.
Eneyskaya, E.V. et al., "Chemo-enzymatic synthesis of 4-methylumbelliferyl β-(1→4)-D-xylooligosides: new substrates for β-D-xylanease assaus," Org. Biomol. Chem., 2005, vol. 3, pp. 146-151.
Fuselier, J.A. et al., "An Adjustable Release Rate Linking Strategy for Cytotoxin-Peptide Conjugates," Bioorganic & Medicinal Chemistry Letters, 2003, vol. 13, pp. 799-803.
Gesson, J.-P. et al., "Prodrugs of anthracyclines for chemotherapy via enzyme-monoclonal antibody conjugates," Anti-Cancer Drug Design, 1994, vol. 9, pp. 409-423.
Haisma, H.J. et al., "A monoclonal antibody-beta-glucuronidase conjugate as activator of the prodrug epirubicin-glucuronide for specific treatment of cancer," Br. J. Cancer, 1992, vol. 66, pp. 474-478.
Haisma, H.J. et al., "A monoclonal antibody-β-glucuronidase conjugate as activator of the prodrug epirubicin-glucuronide for specific treatment of cancer," Br. J. Cancer, 1992, vol. 66, pp. 474-478.
Houba, P.H.J. et al., "Characterization of Novel Anthracycline Prodrugs Activated by Human beta-glucuronidase for Use in Antibody-Directed Enzyme Prodrug Therapy," Biochemical Pharmacology, 1996, vol. 52, No. 3, pp. 455-463.
Houba, P.H.J. et al., "Characterization of Novel Anthracycline Prodrugs Activated by Human β-glucuronidase for Use in Antibody-Directed Enzyme Prodrug Therapy," Biochemical Pharmacology, 1996, vol. 52, No. 3, pp. 455-463.
Huang, P.S. et al., "Drug-targeting strategies in cancer therapy," Current Opinion in Genetics & Development, 2001, vol. 11, pp. 104-110.
Jeffrey, S.C. et al., "Development and Properties of beta-Glucuronide Linkers for Monoclonal Antibody-Drug Conjugates," Bioconjugate Chem., 2006, vol. 17, pp. 831-840.
Jeffrey, S.C. et al., "Development and Properties of β-Glucuronide Linkers for Monoclonal Antibody-Drug Conjugates," Bioconjugate Chem., 2006, vol. 17, pp. 831-840.
Kelly, M.A. et al., "Preparation of some aryl alpha-L-arabinofuranosides as substrates for arabinofuranosides," Carbohydrate Research. 1988, vol. 181, pp. 262-266.
Kelly, M.A. et al., "Preparation of some aryl α-L-arabinofuranosides as substrates for arabinofuranosides," Carbohydrate Research. 1988, vol. 181, pp. 262-266.
Kirschke, H., "Lysosomal Cysteine Peptidases and Malignant Tumours," Cellular Peptidases in Immune Functions and Diseases, Ansorge et al., eds., 1997, Plenum Press, New York, pp. 253-256.
Leenders, R.G.G. et al., "beta-Glucuronyl Carbamate Based Pro-moieties Designed for Prodrugs in ADEPT," Tetrahedron Letters, 1995, vol. 36, No. 10, pp. 1701-1704.
Leenders, R.G.G. et al., "Novel Anthracycline-space-beta-glucuronide, -beta-glucoside, and -beta-galactoside Prodrugs for Application in Selective Chemotherapy," Bioorganic & Medicinal Chemistry, 1999, vol. 7, pp. 1597-1610.
Leenders, R.G.G. et al., "Novel Anthracycline-space-β-glucuronide, -β-glucoside, and -β-galactoside Prodrugs for Application in Selective Chemotherapy," Bioorganic & Medicinal Chemistry, 1999, vol. 7, pp. 1597-1610.
Leenders, R.G.G. et al., "Synthesis and Evaluation of Novel Daunomycin-Phosphate-Sulfate-beta-Glucuronide and -beta-Glucoside Prodrugs for Application in Adept," Bioorganic & Medicinal Chemistry Letters, 1995, vol. 5, No. 24, pp. 2975-2960.
Leenders, R.G.G. et al., "Synthesis and Evaluation of Novel Daunomycin-Phosphate-Sulfate-β-Glucuronide and -β-Glucoside Prodrugs for Application in Adept," Bioorganic & Medicinal Chemistry Letters, 1995, vol. 5, No. 24, pp. 2975-2960.
Leenders, R.G.G. et al., "β-Glucuronyl Carbamate Based Pro-moieties Designed for Prodrugs in ADEPT," Tetrahedron Letters, 1995, vol. 36, No. 10, pp. 1701-1704.
Lougerstay-Madec, R. et al., "Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard," Anti-Cancer Drug Design , 1998, vol. 13, pp. 995-1007.
Marino, C. et al., "Synthesis of 4-methylcoumarin-7-yl beta-D-galactofuranoside, a fluorogenic substrate for galactofuranosidase," Carbohydrate Research, 1995, vol. 276, pp. 209-213.
Marino, C. et al., "Synthesis of 4-methylcoumarin-7-yl β-D-galactofuranoside, a fluorogenic substrate for galactofuranosidase," Carbohydrate Research, 1995, vol. 276, pp. 209-213.
Papot, S. et al., "Design of Selectively Activated Anticancer Prodrugs: Elimination and Cyclization Strategies," Curr. Med. Chem.-Anti-Cancer Agents, 2002, vol. 2, No. 2, pp. 155-185.
Ritter, J.K., "Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions," Chemico-Biological Interactions, 2000, vol. 129, pp. 171-193.
Sanderson et al., "In vivo Drug-Linker Stability of an Anti-CD30 Dipeptide-Linked Auristatin Immunoconjugate," Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, Jan. 15, 2005, pp. 843-852, vol. 11, No. 2.
Schelté, P. et al., "Differential Reactivity of Maleimide and Bromoacetyl Functions with Thiols: Application to the Preparation of Liposomal Diepitope Constructs," Bioconjugate Chem., 2000, vol. 11, pp. 118-123.
Schmidt, F. et al., "Cancer Chemotherapy: A Paclitaxel Prodrug for ADEPT (Antibody-Directed Enzyme Prodrug Therapy)," Eur. J. Org. Chem., 2001, pp. 2129-2134.
Sperker, B. et al., "The Role of beta-Glucuronidase in Drug Disposition and Drug Targeting in Humans," Clin. Pharmacokinet, Jul. 1997, vol. 33, No. 1, pp. 18-31.
Sperker, B. et al., "The Role of β-Glucuronidase in Drug Disposition and Drug Targeting in Humans," Clin. Pharmacokinet, Jul. 1997, vol. 33, No. 1, pp. 18-31.
Stachulski, A.V. et al., "The synthesis of O-glucuronides," Natural Product Reports, 1998, pp. 173-186.
Toshima, K. et al., "Recent Progress in O-Glycosylation Methods and Its Application to Natural Products Synthesis," Chemical Reviews, 1993, vol. 93, No. 4, pp. 1503-1531.
Verdier-Pinard, P. et al., "Sustained Intracellular Retention of Dolastatin 10 Causes Its Potent Antimitotic Activity," Molecular Pharmacology, 2000, vol. 57, pp. 180-187.
Wilbur, D.S. et al., "Biotin Reagents for Antibody Pretargeting. 5. Additional Studies of Biotin Conjugate Design to Provide Biotinidase Stability," Bioconjugate Chem., 2001, vol. 12, pp. 616-623.

Cited By (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8512707B2 (en) 2006-02-18 2013-08-20 Seattle Genetics, Inc. Methods of treating drug-resistant cancers
US20100260786A1 (en) * 2006-02-18 2010-10-14 Seattle Genetics, Inc. Methods of treating drug-resistant cancers
WO2012092616A1 (en) 2010-12-30 2012-07-05 Takeda Pharmaceutical Company Limited Conjugated anti-cd38 antibodies
EP3284755A1 (en) 2010-12-30 2018-02-21 Takeda Pharmaceutical Company Limited Conjugated anti-cd38 antibodies
EP3798231A1 (en) 2010-12-30 2021-03-31 Takeda Pharmaceutical Company Limited Conjugated anti-cd38 antibodies
US11419945B2 (en) 2011-05-27 2022-08-23 Glaxo Group Limited Antigen binding proteins
US9273141B2 (en) 2011-05-27 2016-03-01 Glaxo Group Limited B cell maturation antigen (BCMA) binding proteins
WO2014004376A2 (en) 2012-06-26 2014-01-03 Del Mar Pharmaceuticals Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof
US10188693B2 (en) 2012-08-02 2019-01-29 Stealth Biotherapeutics Corp Methods for treatment of atherosclerosis
WO2014022552A1 (en) 2012-08-02 2014-02-06 Stealth Peptides International, Inc. Methods for treatment of atherosclerosis
US10201585B2 (en) 2012-08-02 2019-02-12 Stealth Biotherapeutics Corp Methods for treatment of atherosclerosis
US20140219956A1 (en) * 2013-02-07 2014-08-07 Immunomedics, Inc. Pro-drug form (p2pdox) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer
US9486536B2 (en) 2013-02-07 2016-11-08 Immunomedics, Inc. Pro-drug form (P2PDOX) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer
US9283286B2 (en) 2013-02-07 2016-03-15 Immunomedics, Inc. Pro-drug form (P2PDox) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer
US9694088B2 (en) 2013-02-07 2017-07-04 Immunomedics, Inc. Pro-drug form (P2PDox) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer
US9095628B2 (en) 2013-02-07 2015-08-04 Immunomedics, Inc. Pro-drug form (P2PDOX) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer
US8877202B2 (en) * 2013-02-07 2014-11-04 Immunomedics, Inc. Pro-drug form (P2PDOX) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer
US11491154B2 (en) 2013-04-08 2022-11-08 Dennis M. Brown Therapeutic benefit of suboptimally administered chemical compounds
US9475874B2 (en) 2013-08-26 2016-10-25 MabVax Therapeutics, Inc. Nucleic acids encoding human antibodies to sialyl-lewisa
EP3906945A2 (en) 2013-08-26 2021-11-10 BioNTech Research and Development, Inc. Nucleic acids encoding human antibodies to sialyl-lewis a
WO2015053871A2 (en) 2013-08-26 2015-04-16 MabVax Therapeutics, Inc. NUCLEIC ACIDS ENCODING HUMAN ANTIBODIES TO SIALYL-LEWISa
US11708412B2 (en) 2013-09-26 2023-07-25 Novartis Ag Methods for treating hematologic cancers
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
US11103593B2 (en) 2013-10-15 2021-08-31 Seagen Inc. Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics
US11116847B2 (en) 2013-12-19 2021-09-14 Seagen Inc. Methylene carbamate linkers for use with targeted-drug conjugates
US10752687B2 (en) 2014-01-24 2020-08-25 Novartis Ag Antibody molecules to PD-1 and uses thereof
US9815898B2 (en) 2014-01-24 2017-11-14 Novartis Ag Antibody molecules to PD-1 and uses thereof
US9683048B2 (en) 2014-01-24 2017-06-20 Novartis Ag Antibody molecules to PD-1 and uses thereof
US11827704B2 (en) 2014-01-24 2023-11-28 Novartis Ag Antibody molecules to PD-1 and uses thereof
US10981990B2 (en) 2014-01-31 2021-04-20 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US11155620B2 (en) 2014-01-31 2021-10-26 Novartis Ag Method of detecting TIM-3 using antibody molecules to TIM-3
US10472419B2 (en) 2014-01-31 2019-11-12 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US10383949B2 (en) 2014-05-28 2019-08-20 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US11141456B2 (en) 2014-05-28 2021-10-12 Stealth Biotherapeutics Corp Therapeutic compositions including frataxin, lactoferrin, and mitochondrial energy generating enzymes, and uses thereof
US10576124B2 (en) 2014-05-28 2020-03-03 Stealth Biotherapeutics Corp Therapeutic compositions including frataxin, lactoferrin, and mitochondrial energy generating enzymes, and uses thereof
US10980890B2 (en) 2014-05-28 2021-04-20 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US9993568B2 (en) 2014-05-28 2018-06-12 Legochem Biosciences, Inc. Compounds comprising self-immolative group
US9919057B2 (en) 2014-05-28 2018-03-20 Legochem Biosciences, Inc. Compounds comprising self-immolative group
EP3501532A2 (en) 2014-05-28 2019-06-26 Stealth BioTherapeutics Corp Therapeutic compositions including frataxin, lactoferrin, and mitochondrial energy generating enzymes, and uses thereof
EP3502132A1 (en) 2014-05-28 2019-06-26 Stealth BioTherapeutics Corp Therapeutic compositions including therapeutic small molecules and uses thereof
US9856324B2 (en) 2014-06-04 2018-01-02 MabVax Therapeutics, Inc. Human monoclonal antibodies to ganglioside GD2
US10906988B2 (en) 2014-06-04 2021-02-02 Biontech Research And Development, Inc. Human monoclonal antibodies to ganglioside GD2
EP3868405A1 (en) 2014-06-04 2021-08-25 BioNTech Research and Development, Inc. Human monoclonal antibodies to ganglioside gd2
US11760809B2 (en) 2014-06-04 2023-09-19 BioNTech SE Human monoclonal antibodies to ganglioside GD2
WO2015187811A2 (en) 2014-06-04 2015-12-10 MabVax Therapeutics, Inc. Human monoclonal antibodies to ganglioside gd2
US10973920B2 (en) 2014-06-30 2021-04-13 Glykos Finland Oy Saccharide derivative of a toxic payload and antibody conjugates thereof
US11344620B2 (en) 2014-09-13 2022-05-31 Novartis Ag Combination therapies
WO2016077260A1 (en) 2014-11-10 2016-05-19 Bristol-Myers Squibb Company Tubulysin analogs and methods of making and use
CN107249643A (zh) * 2014-12-09 2017-10-13 艾伯维公司 具有细胞渗透性的bcl‑xl抑制剂的抗体药物缀合物
CN113209306A (zh) * 2014-12-09 2021-08-06 艾伯维公司 具有细胞渗透性的bcl-xl抑制剂的抗体药物缀合物
WO2016115201A1 (en) 2015-01-14 2016-07-21 Bristol-Myers Squibb Company Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using
US10118965B2 (en) 2015-09-25 2018-11-06 Legochem Biosciences, Inc. Compositions and methods related to anti-EGFR antibody drug conjugates
US10183997B2 (en) 2015-09-25 2019-01-22 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
US11167040B2 (en) 2015-11-25 2021-11-09 Legochem Biosciences, Inc. Conjugates comprising peptide groups and methods related thereto
US11173214B2 (en) 2015-11-25 2021-11-16 Legochem Biosciences, Inc. Antibody-drug conjugates comprising branched linkers and methods related thereto
US11413353B2 (en) 2015-11-25 2022-08-16 Legochem Biosciences, Inc. Conjugates comprising self-immolative groups and methods related thereto
US11229708B2 (en) 2015-12-04 2022-01-25 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11844839B2 (en) 2016-03-25 2023-12-19 Seagen Inc. Process for the preparation of pegylated drug-linkers and intermediates thereof
US10640563B2 (en) 2016-06-08 2020-05-05 Abbvie Inc. Anti-B7-H3 antibodies and antibody drug conjugates
US11712480B2 (en) 2016-08-03 2023-08-01 Pfizer Inc. Heteroaryl sulfone-based conjugation handles, methods for their preparation, and their use in synthesizing antibody drug conjugates
WO2018025168A1 (en) 2016-08-03 2018-02-08 Pfizer Inc. Heteroaryl sulfone-based conjugation handles, methods for their preparation, and their use in synthesizing antibody drug conjugates
WO2018035391A1 (en) 2016-08-19 2018-02-22 Bristol-Myers Squibb Company Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use
WO2018075842A1 (en) 2016-10-20 2018-04-26 Bristol-Myers Squibb Company Condensed benzodiazepine derivatives and conjugates made therefrom
WO2018138591A1 (en) 2017-01-24 2018-08-02 Pfizer Inc. Calicheamicin derivatives and antibody drug conjugates thereof
US11730822B2 (en) 2017-03-24 2023-08-22 Seagen Inc. Process for the preparation of glucuronide drug-linkers and intermediates thereof
US11654197B2 (en) 2017-03-29 2023-05-23 Legochem Biosciences, Inc. Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
WO2019035970A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES FOR USE AS TOLL 7 RECEPTOR IMMUNOSTIMULATING AGONISTS (TLR7)
WO2019035968A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS TOLL RECEPTOR 7 (TLR7) AGONISTS AS IMMUNOSTIMULANTS
WO2019035971A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS TOLL 7 RECEPTOR IMMUNOSTIMULATING AGONISTS (TLR7)
WO2019036023A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS IMMUNOSTIMULANT TOLL (TLR7) RECEPTOR 7 AGONISTS
WO2019035969A1 (en) 2017-08-16 2019-02-21 Bristol-Myers Squibb Company TOLL RECEPTOR 7 (TLR7) AGONISTS COMPRISING A TRICYCLIC FRAGMENT, CONJUGATES CONTAINING SAME, RELATED METHODS AND USES THEREOF
WO2019073069A1 (en) 2017-10-13 2019-04-18 Boehringer Ingelheim International Gmbh HUMAN ANTIBODIES AGAINST THOMSEN-NEW ANTIGEN (TN)
WO2019209811A1 (en) 2018-04-24 2019-10-31 Bristol-Myers Squibb Company Macrocyclic toll-like receptor 7 (tlr7) agonists
US11827703B2 (en) 2018-05-09 2023-11-28 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
US11911483B2 (en) 2018-05-29 2024-02-27 Bristol-Myers Squibb Company Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making
US10898578B2 (en) 2018-05-29 2021-01-26 Bristol-Myers Squibb Company Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making
WO2019231879A1 (en) 2018-05-29 2019-12-05 Bristol-Myers Squibb Company Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making
WO2020028608A1 (en) 2018-08-03 2020-02-06 Bristol-Myers Squibb Company 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS AND METHODS AND USES THEREFOR
WO2020028610A1 (en) 2018-08-03 2020-02-06 Bristol-Myers Squibb Company 2H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS AND METHODS AND USES THEREFOR
US11707533B2 (en) 2019-09-04 2023-07-25 Legochem Biosciences, Inc. Antibody-drug conjugate comprising antibody against human ROR1 and use for the same
US11759527B2 (en) 2021-01-20 2023-09-19 Abbvie Inc. Anti-EGFR antibody-drug conjugates

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